Figure 2:  A schematic representation of normal (A), Alzheimer’s (B), and high superior autobiographical memory (C) brain along with unaffected (bold black) or
affected (bold red) regions. Magnetic resonance imaging (MRI) of normal (A’) and Alzheimer’s disease (B’) brain. Histopathological findings in normal (A’’) and
Alzheimer’s disease (B’’) brain tissue stained with Thioflavine-S (Arrow, senile plaque; arrowheads, neurofibrillary tangles).
    
    

Elucidating the cognitive and biochemical changes that accompany these changes remains an area of intense investigation [34-36]. Because failure of clinical trials has been attributed to testing of potential disease-modifying therapeutic agents too late, research has focused on identifying the most prominent and earliest cognitive, behavioral, and structural brain symptoms to early intervention. By using voxel-based morphometry (VBM) and shape analysis of magnetic resonance imaging (MRI) data, it has been shown that individuals with pre-clinical AD and MCI have significantly reduced brain volume, not only in the medial temporal lobes, but also in the posterior cingulate/precuneus, and orbitofrontal cortex compared with control individuals [37]. Moreover, using VBM cross-sectional analysis, it has demonstrated that in progressive MCI, patients revealed cerebral areas of lower grey matter volume in the parahippocampal gyrus, precuneus, and posterior cingulate 12 months prior to AD diagnosis [38]. Recently, Khan et al. [39] have implicated the lateral entorhinal cortex as the earliest area of the brain to be affected in pre-clinical AD.

Taken together, these observations comply with the notion that structural brain changes occur (10-12) years before clinical, cognitive decline in AD [40,41], and that brain changes are indicative of decreased synaptic density, neuronal loss, brain atrophy, which interrupt the neuronal network, which is critical for declarative (episodic) memory [42]. However, others have found greater atrophy in the hippocampus, predominantly in the CA1 region and subiculum and entorhinal cortex [43-45].

These discrepancies in diagnostic accuracy might reflect either differences between the methods used [46] or variability of which marker is used (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric:” visual, manual, semi-automated, or automated segmentation/ computation) [47]. Furthermore, a number of challenges must be overcome before the medical community can attempt to intervene identified pre-clinical subjects to delay and even prevent emergence of the clinical syndrome [48]. Therefore, further investigation is needed to clarify these issues.

Recognizing that, the pathophysiological process of AD begins years, if not decades, prior to clinically obvious symptoms (i.e., preclinical stage of AD) calls into question the definition of AD. Simply put, the difference lies in whether AD is really a neurodegenerative disease or whether it better qualifies as a neurodevelopmental disorder, especially in those subjects who carry fully penetrant genetic alterations that result in familial Alzheimer’s disease (FAD) (e.g., Colombian kindred bearing with autosomal dominant/recessive mutation in PSEN-1 [49,50]). This last issue is a pressing one to be answered given its definitive impact on therapeutic outcomes and in memory research.

In conclusion, the study of the aforementioned cases (e.g., H.M., C.W., A.D) [22,26] and other relevant ones with amnesia (e.g., R.B., G.B., E.P) [51] generally reveal that inflicted damage to MTL from surgery, infection, neurodegenerative disease, or by other causes (e.g., stroke, tumor, drugs, hypoxia) disturbs the brain to form long- term memories. Amnesic patients, but not advanced AD patients, are still able to retain working (short-term) and implicit (procedural) memory regardless of MTL structures. Specifically, bilateral damage to any single component of the hippocampal formation, including the hippocampus (e.g., bilateral lesion of the entire CA1 field of the hippocampus), dentate gyrus, subiculum, and adjacent structures such as the entorhinal, perirhinal, and parahippocampal cortices, might be sufficient to produce clinically significant and readily detectable memory impairment.

Undoubtedly, the study of anterograde and retrograde amnesia has led to the traditional idea that MTL structures are involved in the formation of LTM and that immediate memory, which refers to the limited amount of information that can be held in the mind when material is presented for learning, and working memory are independent of these structures. However, Ranganath and Blumenfield [52] and Graham et al. [53] have revisited this idea. Basically, these authors proposed that MTL, in addition to its established role in forming LTM, is needed for at least some kinds of working memory, and that the perirhinal cortex is needed for certain kinds of visual perception. Jeneson and Squire (2012) and Jeneson et al. (2011) have in turn reappraised this notion [54]. They have reached the conclusion that performance on tasks depends on LTM even when the retention interval is brief.

Therefore, the authors have elegantly proposed that MTL lesions impair performance only when immediate memory and working memory (the capacity to maintain a limited amount of information through active rehearsal, usually across short time) are overloaded with information to support performance. Additionally, they introduce the notion that a short-term delay task (subspan memoranda) is supported by immediate memory and working memory and are independent of the MTL. Furthermore, the view that the hippocampus and other medial temporal lobe structures are linked to both memory and spatial cognition has also been reexamined. Kim et al. have shown that memory and spatial cognition can be two separate entities [55]. Indeed, the researchers carried out studies of path integration in patients with medial temporal lobe lesions. Individuals entered a circular arena without vision, searched for a target, and then attempted to return to the start location. The patients performed accurately as well as the controls. This result has been interpreted as their ability to construct a coherent working memory of spatial environments.

Additionally, it has been demonstrated that structures other than the hippocampus can support face recognition memory in patients with hippocampal lesions [56] and “fast mapping” tasks [57]. Interestingly, Smith and coworkers [58] have quantitatively found an orderly relationship between anterograde and retrograde amnesia, such that the patients bearing bilateral MTL lesions with more severe anterograde amnesia had more extensive retrograde amnesia. However, whether amnesia is due to a deficit of encoding, storage, or retrieval is not yet fully understood. Therefore, further investigation is needed to solve these issues. This is of paramount importance for therapeutic approaches to prevent, protect, and improve memory and cognitive performance not only in amnesic but also in AD patients.

The bright side of memory

“I run my entire life through my head every day and it drives me crazy!!!...” A.J.

Jill Price (1965 – present) is the first person to be recognized by the scientific (known as A.J.) and public (known as The woman who can’t forget, [59]) community to possess highly superior autobiographical memory (HSAM), a phenomenon previously known as hyperthymesic syndrome [60]. HSAM is a rare condition in which individuals are able to recall events from their personal past, including the days and dates on which they occurred, with very high accuracy. Indeed, Price can recall in vivid detail events (i.e., she can evoke what day of the week a particular date fell on within her mental calendar) from her past since age 12 in a “nonstop, uncontrollable, and automatic” fashion. Extensive neuropsychological studies have not only demonstrated Price’s memory superiority (e.g., General Memory Index on Wechsler Memory Scale-Revised: score = 122, 1.5 SD above average, Autobiographical Memory Index: score 27/27, (Table 1), but they have also revealed atypical brain lateralization (i.e., although Price insisted she is right-handed, she showed left-handed dominance on several tasks) and atypical variant in neuropsychological tests, which suggested some brain areas with noticeable strengths (e.g., medial temporal lobe) and weaknesses (e.g., pre-frontal and frontal lobe, anterior left hemisphere).

Despite these observations, she also displayed other neuropsychological domains (e.g., calculations, motor speed, visual, spatial, and language) within the normal range (within 1.5 SD). These findings were interpreted by Dr. McGaugh’s research team, who suggested that Jill Price might have a variant of a neurodevelopmental, frontostriatal system disorder which includes obsessive-compulsive disorder (OCD), thus explaining her diagnosis of hyperthymesic syndrome [60].

Further studies by the same research group have identified ten additional cases of HSAM individuals. The eleven individuals (including J.P.) excelled in several cognitive assessments, such as autobiographical memory task, recall of names paired with faces, visual memory test, logical memory free-recall test, and Leyton Obsessional Inventory Score-Short compared to control individuals. However, HSAM individuals showed no differences in forward and backward digit span test, visual reproduction test, and logical memory recognition test compared to control group [61].

Remarkably, the investigation revealed both behavioral and neuroanatomical domain commonalities among HSAM participants. First, it was verified that HSAM individuals have an impressive memory for autobiographical events and extensive knowledge of public event information. Second, for the typical HSAM participant, the range of dates for which the days and dates are recalled is limited to dates within their lifetime, and in particular from the age of 10.5 years old, a mean age at which HSAM individuals became aware of their ability to remember events from most days. Third, most of the HSAM participants (9/11) tend to display a degree of OCD. Fourth, as reported previously with the “A.J.” case, HSAM participants showed no differences in their performance on digit-span forward, verbalpaired associates, and visual reproduction, but performed significantly better than controls on the Logical Memory test free-recall and Names-to-Faces test. It was concluded that HSAM individuals “do not possess a domain-general, highly effective ability to encode and retrieve new information. Instead, it is more domain-specific as even those tests in the cognitive battery in which they outperform controls can be viewed in a personal, autobiographical manner.…” [61]. Finally, by using four structural imaging analyses (e.g., Voxel based morphometry-gray matter, voxel based morphometry-white matter, tensor based morphometry, diffusion tensor imaging-fractional anisotropy), unusual structural differences (i.e., expanded regions) were found in the HSAM participants in the region of the inferior and middle temporal gyri and temporal pole, the anterior insula, the parahippocampal gyrus, inferior parietal sulcus, uncinate fascicle, anterior putamen, caudate and posterior pallidum [61] (Figure 2C).

The authors suggested that it was highly plausible that all these regional brain differences, and especially the medial temporal lobe and uncinate fascicle, might not only contribute to explain the HSAM participants’ exceptional autobiographical memory, but also their behavioral trend towards OCD tendencies. In support of the former idea, it is noteworthy that patients with bilateral lesions to the medial temporal lobe (as discussed above for H.M. and C.W.) demonstrated retrograde memory loss, for both public and personal autobiographical facts and events.

Therefore, it is highly conceivable that HSAM individuals rely upon these regions to excel in autobiographical memory. Because HSAM individuals distinguish themselves by their ability to retain what they do learn, this provided an appealing framework in cognition-based intervention research (e.g., [62-64]. Molecularly, how the brain produces a “superior memory” is still a fascinating enigma.

“I have so many things to me that you can’t even guess them all” K.P.

Kim Peek (1951 – 2009) was born with macrocephaly, damage to the cerebellum, and agenesis of the corpus callosum. He was diagnosed with savant syndrome. Formally, the disorder is a rare but spectacular condition in which persons with developmental disabilities, including but not limited to autism, or other CNS disorders or diseases have some outstanding “island of genius” that stands in marked contrast to overall physical disability [65]. Notably, the extraordinary talents associated with prodigious savants are invariably linked to memory.

Particularly, K.P. is known as “mega-savant” because of his unlimited memory capacity. Given the fact that he read a page in 8- 10 seconds, it was suggested that Peek had learned at least 9,000 books recalling their content with 97% accuracy, decades later. Interestingly, he apparently understood the material he had memorized. K.P. also displayed numerous skills, including calendar calculating, lightningspeed calculation abilities, piano performance, and encyclopedic knowledge in several topics (e.g., world and American history, geography, literature, music, among others) [66]. Despite the fact that Kim’s memory itself could be considered his savant skill, he had trouble following directions and focusing, showed poor social skills and verbal communication skills, as described by the scientist he met in 2006 [67]. Moreover, one of his greatest difficulties was abstraction or conceptual thinking. Indeed, as concluded by Dr. V.S. Ramachandran (Neuroscientist, University of California, San Diego) and his research team after conducting several tests on K.P. to evaluate conceptual encoding: “…What’s exciting about these results is- and what it’s showing you already- is that Kim, it turns out, is not editing, censoring, and encoding the information in the same way that normal people do, and it’s this lack of conceptual encoding that makes some of these savants adhere slavishly to every little detail and actually improves their memory in some respects, but of course they are paying a price for it…”, furthermore, “…[his] tendency to take metaphors literally, is another example of a failure of conceptual encoding…”According to Dr. Rita Jeremy (University of California, San Francisco) “… Altogether, he is a very unusual profile that cannot be summed up in any single score…” [67].

Sadly, K.P. died of a heart attack in his hometown Salt Lake City at the age of 58. Kim inspired the movie “Rain Man”, a 1988 film directed by Barry Levinson, starring Dustin Hoffman and Tom Cruise, several (~19) documentaries, and a book written by his father captured his real nature [68]. However, in comparison to other important cases (e.g., [11,69]), not a single scientific article (to our knowledge) has been published in a peer-reviewed journal reporting K.P.’s case. However, it is revealing to hear Dr. V.S. Ramachandran ask him, “How do you do that?” [i.e., the memory process, indeed]. Kim fancifully addressed the answer to his father (Francis Peek) by asserting that “They are still unable to find out what all of this is about, aren’t they dad?” [67]. This is not surprising. Savants are puzzled too! And normally cannot explain how they perform their skills. To date, no information is available to establish whether Kim’s brain was preserved to perform further post-mortem histological analysis.

Still, several questions remain unanswered. What brain anatomical structure(s) provided Kim’s skills? Did the size, shape, and neuronal structure of his hippocampus deviate from normal? Was his neural network hyper-connected? Was Kim intelligent? Surely he was, but how then to define him? [70]. Unquestionably, K.P. was “single brained.” Is it possible to conciliate the assumption that savant abilities arise from left brain injury with right brain compensation in a unified brain, as found in Kim’s? Although recent experimental observations with transcranial direct current stimulation [71] and new “acquired” savant skills suggest that the theory is a valid lead for further investigation, it seems not to apply to Kim. Can humans attain the talent of a savant without sacrificing everyday function? Last, but not least, is it possible to design a “better” brain? [72,73]. To further complicate matters, a study conducted by Opitz and coworkers suggests that K.P. probably had FG syndrome [74]. FGS, also known as Opitz–Kaveggia syndrome [75] is a rare genetic syndrome caused by one or more recessive genes located on the X chromosome and causing physical anomalies and developmental delays including retardation, hyperactivity, hypotonia, a characteristic facial appearance and macrocephaly (e.g., [76]). However, neither cytogenetic analysis nor formal neuropsychological data nor additional diagnostic tests from Kim are available to confirm or dismiss such a claim.

We conclude that K.P.’s skills were probably due to the assembly of the four operations of explicit memory- “deep” encoding, storage, consolidation, and retrieval, in one processing unit; whereas J.P.’s HSAM might be caused by a highly-self focused storage and consolidation of episodic events, somehow “contaminated” or “intruded” by an overpowering unconscious retrieval of daily life futile details. We also conclude that in contrast to the majority of savant individuals, being HSAM does not modify professional development, social life, or lifestyle (e.g., Marilu Henner, actress; Aurelien Hayman, student at Durham University, UK; Louise Owen, violinist). Whether it would be a privilege or a burden to possess a superior memory is a personal viewpoint. According to Jill Price, this is an affliction.

Ultimately, these cases suggest that the way the brain is wired will probably determine how “successful” a person would be with his/her interpersonal relationships. We think that, despite the high complexity of our brain, which might be portrayed with the recurrent question “How do you do that?”in the cognitive field, Jill Price’s“ super memory” is a unique opportunity to enlighten basic (e.g., [77]) and pharmaceutical research (e.g., [78,79]) to define new methods to improve our memory focused on more practical and professional activities and, perhaps one day by the same means, to prevent memory loss in subjects with high risk of suffering from either familial or sporadic AD. Nonetheless, before this can happen, the molecular mechanisms of memory have to be fully elucidated and pharmaceutical targets have to be established. We review this last issue next.

Memory: in search of its molecular basis

As a pioneer of the biology of mind research, Dr. Kandel ER has used the living sea slug Aplysia californica to demonstrate the molecular, cellular, and circuit mechanisms that underlie the learning and memory processes. During the last 15 years, he has unprecedentedly popularized the molecular basis of memory, (i.e., How memories are made, stored, retrieved, and lost in the renowned textbook chapter “Cellular mechanisms of implicit memory storage and the biological basis of individuality”, published in the Principles of Neural Science [80]); and this topic has been reviewed extensively [81-88]. Also, an inspiring historical account of a personal quest to unlock the biological basis of memory is outlined in his book “In search of memory. The emergence of a new science of mind.” [89].

Several outstanding observations from Kandel’s work can be highlighted. First, based on stimuli of the siphon and/or tail and gill-withdrawal reflex response in Aplysia, he and his team worked to establish the cellular and molecular mechanisms of habituation, sensitization, and classical conditioning. Basically, habituation is the result of drastic decrease in the strength of synaptic transmission from excitatory (glutamatergic) sensory neurons, interneurons, or both to the motor neurons; depending on the duration of stimuli, it can lead to short-term or long-term habituation. Interestingly, anatomical studies showed that long-term habituation resulted from a decrease in the number of synaptic contacts between sensory and motor neurons [90]. In contrast, sensitization results from an increase in synaptic transmission at several connections in the neural circuit made by sensory neurons with serotonergic interneurons and motor neurons. Through serotonin binding receptor (SBR, neurotransmitter receptor (NTR) in Figure 3) coupled to G proteins, serotonin (5- HT; neurotransmitter (NT) in Figure 3) triggers the activation of two parallel pathways: 5-HT > SBR> G_s > adenyl cyclase (+ATP) > cAMP > cAMP-dependent PKA > K+ channels > Ca²⁺; and 5-HT > SBR> G_q/11 >PLC > diacylglycerol > PKC. As noted, activation of PKA and PKC kinases results in sustained release of neurotransmitters (glutamate) from the sensory neuron to motor neuron, and a strong gill-withdrawal reflex is induced. Sensitization can also be short-term or long-term. In classical conditioning, a withdrawal reflex of Aplysia is greater and longer-lasting enhancement. Classical conditioning involves two paired stimuli: a conditioned stimulus (CS), which is harmless to the organism (e.g., a light, a tone, a touch), and produces no overt response unrelated to the response that will be learned; an unconditioned stimulus (US), which is also harmless, but induces a strong and sustained response (e.g., salivation). Importantly, repeated pairing of the CS and US causes the CS to become an anticipatory signal for the US.

Figure 3: A schematic representation of the molecular mechanism of memory consolidation in normal (A), Alzheimer’s disease (B), and high superior autobiographical memory(C). For detail, see text. Abbreviations: NT: Neurotransmitter; NTR: Neurotransmitter Receptor; AC: Adenylyl Cyclase; PKA(a) or PKA(i): Protein Kinase A Active or Inactive; MAPK: Mitogen-activated Protein Kinase; CREB-1 and CREB-2: cAMP Response Element Binding Protein; CBP: CREB-binding Protein; CRE: cAMP Response Element; CAAT: CAAT Box; C/EBP: CAAT Box Enhancer Binding Protein; ATF: Activating Transcription Factor; A: Actin; T: Tubulin; CPEB: Cytoplasmic Polyadenylation Element-binding Protein; Aβ: Amyloid-beta; ND-SD: Neuronal Death-synaptic Dysfunction; NS: Normal-synapsis; HS: Hyper-synapsis

    

    

    Figure 3:  A schematic representation of the molecular mechanism of memory consolidation in normal (A), Alzheimer’s disease (B), and high superior autobiographical
memory(C). For detail, see text.
Abbreviations: NT: Neurotransmitter; NTR: Neurotransmitter Receptor; AC: Adenylyl Cyclase; PKA(a) or PKA(i): Protein Kinase A Active or Inactive; MAPK:
Mitogen-activated Protein Kinase; CREB-1 and CREB-2: cAMP Response Element Binding Protein; CBP: CREB-binding Protein; CRE: cAMP Response Element;
CAAT: CAAT Box; C/EBP: CAAT Box Enhancer Binding Protein; ATF: Activating Transcription Factor; A: Actin; T: Tubulin; CPEB: Cytoplasmic Polyadenylation
Element-binding Protein; Aβ: Amyloid-beta; ND-SD: Neuronal Death-synaptic Dysfunction; NS: Normal-synapsis; HS: Hyper-synapsis
    
    

Close

Second, Kandel’s lab demonstrated that the conversion of short- term memory into long-term memory (i.e., consolidation) requires de novo messenger RNAs, and protein synthesis in the neurons (sensory neurons) and in facilitating interneurons (sensory neuron- motor neuron circuit), producing the growth of new synaptic connections between sensory neurons and motor neurons. Briefly, the mechanism involved in the prolonged activation of PKA via 5-HT/ SBP/Gs, allows the catalytic subunit of PKA kinase to translocate into the nucleus of the sensory neurons. Once there, active PKA in the presence of ATP activates mitogen-activated protein kinase (MAKP), which phosphorylates the transcription repressor CREB-2 (cAMP response element binding protein) liberating the transcription factor CREB-1. This unrepressed factor, in turn, binds a promoter element, CRE (cAMP response element), which together with the coactivator CREB-binding protein (CBP) turn on specific genes. Two important genes are essentially expressed for long term-facilitation: ubiquitin carboxiterminal hydrolase, which facilitates ubiquitinmediated protein degradation, thereby increasing activation of PKA; and the transcription factor C/EBP (CAAT box enhancer binding protein), which can form both homodimers with itself and form heterodimers with activating transcription factor (e.g., ATF4). These complex factors, in turn, act on downstream genes such as N-actin and tubulin, which cause the growth of new synaptic connections that support long-term memory (Figure 3A).

Third, it was found that alterations in the molecular component(s) of long-term memory not only affect Aplysia but also other model systems such as mice/rat and fly Drosophila melanogaster. Indeed, it has been found that either up-regulation of dominant active CREB- 1 mutants in mice [91], or expression of constitutively active CREB protein in Aplysia [92] and in rat [93,94] increase long-term synaptic potentiation/plasticity and memory storage. In contrast, inhibition of CREB-1 by CREB-2 in Drosophila [95], inhibition of ATF and C/EBP [96] or expression of a truncated form of CBP in mice [97] exhibited deficit in synaptic plasticity and memory storage.

Together, these observations suggest that the machinery for shortterm and long-term memory is conserved through evolution (Table 2). Fourth, Kandel and co-workers elegantly explained the molecular mechanism implicated in storage for long-term memory. They found that 5-HT increases (by an undetermined mechanism involving PKA and Phosphoinositide 3-kinase, PI3K) the synthesis of Aplysia CPEB (cytoplasmic polyadenylation element-binding protein) at the synaptic terminal of sensory neurons, working as a regulator of local protein synthesis [98]. Interestingly, the induction of CPEB is independent of transcription, probably via PI3K, but requires new protein synthesis via PKA. Most intriguingly, it was found that CPEB has prion-like properties, (i.e., self-perpetuating molecule [99,100]). Recently, Raveendra et al. have shown that Aplysia CPEB can exist as an alpha-helix–rich and a beta-sheet–rich amyloid (aggregated) conformational structures [101].

Table 2: Comparison of protein sequences involved in learning and memory by basic local alignment search tool (BLAST) in human (Homo sapiens), snail (Aplysia californica), and fly (Drosophila melanogaster). Abbreviations: AC: Adenylate Cyclase; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor; C/EBP: CCAAT-box-enhanced Binding Protein; CaMKII: Ca2+/Calmodulin Protein Kinase II; CaMAC: Ca2+/calmodulin-activated Adenylyl Cyclase; Ca-i-PKC: Ca2+-independent PKC; CN: Calcineurin; CPEB: Cytoplasmic Polyadenylation Element Binding Protein; DAR: Dopamine Receptor; PLC: Phospholipase C; PP1: Protein Phosphatase-1; PKA: Protein Kinase A; PKC:Protein Kinase C; NMDAR: N-methyl-D-aspartate Receptor; UH: Ubiquitin Hydroxylase; 5-HT-R: Serotonin Receptor

  

    
Specie/ 
      
Protein 
      
Name 
    
Homo 
      
sapiens 
    
Accession 
      
number 
    
Aplysia 
      
californica 
    
Accession 
      
number 
    
Drosophila 
      
melanogaster 
    
Accession 
      
number
    
Hs vs Ac 
      
BLAST result:
      
Identity, %;
      
Similarity, %; (E) 
    
Hs vs Dm 
      
BLAST result:
      
Identity, %;
      
Similarity, %; (E)
  
  

    
CaMAC 
    
AC type 1
    
Q08828.2
    
AC
    
NP_001191588.1
    
Ca(2+)/calmodulin
      
-responsive
      
adenylate cyclase
    
P32870.2
    
40%; 57%; (0.0)
    
46%; 64%; (1x10-112)
  
  

    
ACtype    8
    
P40145.1
    
AC
    
NP_001191588.1
    
Ca(2+)/calmodulin
      
-responsive
      
adenylatecyclase
    
P32870.2
    
40%; 58%; (0.0)
    
58%; 76%; (6x10-139)
  
  

    
PKA
    
PKA alpha
      
(beta)
    
P17612.2
    
Catalytic subunit of PKA
    
NP_001191420.1
    
PKA c1
      
Isoform B (C,D)
    
AAN10703.1
    
85%; 92%; (0.0)
    
82%; 89%; (0.0)
  
  

    
PKA gamma
    
P22612.3
      
P22612.3
      
P22612.3
    
Catalytic subunit of PKA
    
NP_001191420.1
    
PKA c1
      
Isoform B (C,D)
    
AAN10703.1
    
74%; 87%; (0.0)
    
75%; 85%; (0.0)
  
  

    
PKC
    
PKCepsilon
    
CAA46388.1
    
Ca-i-PKC 
    
NP_00119140.1.1 
    
PKC
    
P13678.1
    
63%; 77%; (0.0)
    
60%; 74%; (0.0)
  
  

    
PKC alpha
    
EAW89014.1
    
Ca-i-PKC
    
NP_00119140.1.1
    
PKC 
    
P13678.1
    
64%; 78%; (1x10-155)
    
63%; 79%; (8x10-154)
  
  

    
PKC gamma
    
EAW72161.1
    
Ca-i-PKC
    
NP_00119140.1.1
    
PKC
    
P13678.1
    
58%; 75%; (3x10-129)
    
44%; 57%; (8x10-144)
  
  

    
PKC eta 
    
AAH37268.1
    
Ca-i-PKC
    
NP_00119140.1.1
    
PKC
    
P13678.1
    
54%; 69%; (0.0)
    
55%; 68%; (0.0)
  
  

    
PKC beta
    
AAH36472.1
    
Ca-i-PKC
    
NP_00119140.1.1
    
PKC
    
P13678.1
    
61%; 76%; (1x10-149)
    
63%; 70%; (1x10-153)
  
  

    
PKC iota
    
AAB17011.1
    
Ca-i-PKC
    
NP_00119140.1.1
    
PKC
    
P13678.1
    
43%; 58%; (1x10-135)
    
43%; 57%; (3x10-136)
  
  

    
PKC zeta 
    
AAA36488.1
    
Ca-i-PKC
    
NP_00119140.1.1
    
PKC
    
P13678.1
    
44%; 58%; (3x10-129)
    
43%; 60%; (6x10-135)
  
  

    
PKCtheta
    
AAI13360.1
    
Ca-i-PKC
    
NP_00119140.1.1
    
PKC
    
P13678.1
    
43%; 58%; (0.0)
    
46%; 62%; (0.0)
  
  

    
PKC mu
    
CAA53384.1
    
Ca-i-PKC
    
NP_00119140.1.1
    
PKC
    
P13678.1
    
30%; 49%; (8x10-31)
    
30%; 49%; (6x10-31)
  
  

    
PP-1
    
PP-1 
    
AAA36508.1
    
PP-1 
    
XP_005105569.1 
    
PP-1
    
CAA39820.
    
42%;54%; (0.018)
    
88%; 92%; (0.0)
  
  

    
UH
    
UHisozyme L1
    
P09936.2
    
UH
    
NP_001191493.1
    
UH36
    
Q9VRP5.3
      
 
    
43%; 62%; (1x10-58)
    
50%; 70%; (8.9)
  
  

    
PLC
    
PLC beta1 
    
AAF86613.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
38%; 54%; (4x10-45)
    
50%; 68%; (1x10-140) 
  
  

    
PLC beta2 
    
AAP35551.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
33%; 53% (8.6)
    
41%; 60%; (2x10-48)
  
  

    
PLC beta3 
    
CAA85776.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
38%;55%; (2x10-44)
    
46%; 63%; (0.0)
  
  

    
PLC beta4 
    
AAI43869.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
37%; 56% (2x10-49)
    
46%; 64%; (3x10-128)
  
  

    
PLC delta1 
    
AAA73567.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
38%;55%; (2x10-73)
    
46%; 59%; (1x10-58)
  
  

    
PLC delta3 
    
AAH72384.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
36%;51%; (2x10-62)
    
35%; 52%; (2x10-55)
  
  

    
PLC delta4 
    
AAH06355.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
37%;56%; (2x10-75)
    
45%; 61%; (4x10-63)
  
  

    
PLC epsilon1 
    
AAI51855.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
34%; 52%; (1x10-38)
    
42%; 58%; (6x10-43)
  
  

    
PLC gamma1 
    
AAI44137.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
32%; 50%; (2x10-45)
    
44%; 58%; (6x10-47)
  
  

    
PLC gamma2 
    
AAQ76815.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
31%; 50%; (4x10-42)
    
34%; 50%; (2x10-49)
  
  

    
PLC eta
    
AAI13951.1
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
41%;60%; (2x10-83)
    
29%; 46%; (5x10-88)
  
  

    
PLC zeta
    
AAN71895.1
      
 
    
PLC
    
NP_001191617.1
    
PLC
    
AAA28820.1
    
47%; 65%; (2x10-65)
    
38%; 56%; (4x10-53)
      
 
  
  

    
C/EBP
    
C/EBP gamma
    
AAC50201.1
    
ApC/EBP 
    
NP_001191392.1
    
C/EBP
    
AAA28415.1
    
45%; 72%; (86x10-19)
    
40%; 73%; (4x10-15) 
  
  

    
C/EBP delta
    
EAW86679.1
    
ApC/EBP
      
 
    
NP_001191392.1
    
C/EBP
    
AAA28415.1
    
38%; 69%; (1x10-14)
    
40%; 70%; (2x10-16) 
  
  

    
C/EBP beta
    
EAW75629.1
    
ApC/EBP
      
 
    
NP_001191392.1
    
C/EBP
    
AAA28415.1
    
45%; 63%;(4x10-18)
    
44%; 68%; (1x10-16)
  
  

    
C/EBP épsilon
    
EAW66183.1
    
ApC/EBP
      
 
    
NP_001191392.1
    
C/EBP
    
AAA28415.1
    
30%; 50%; (6x10-17)
    
43%; 64%; (1x10-15)
  
  

    
C/EBP zeta
    
AAH34475.1
    
ApC/EBP 
    
NP_001191392.1
    
C/EBP
    
AAA28415.1
    
29%;40%; (2.6)
    
34%; 48%; (0.078)
  
  

    
CaMKII- 
    
CaMKII- 
    
AAH40457.1
    
CaMKII- 
    
ACN43221.1
    
CaM-kinase II alpha
    
Q00168.1
    
78%; 88%; (0.0)
    
71%; 81%; (0.0)
  
  

    
CN
    
CN
    
AAC37581.1
    
CN B homologous protein 1-like 
    
XP_005095982.1 
    
CN A1,
      
isoform A (D)
    
AAF57105.3
    
26%; 51%; (0.90)
    
24%; 48%; (1.8)
  
  

    
CN
    
AC37581.1
    
 
    
 
    
CN B,
      
isoform A (B)
    
AAF46026.1
    
 
    
36%; 50%; (4.6)
  
  

    
CPEB
    
CPEB1
    
Q9BZB8.1
    
CPEB 
    
NP_001191467.1 
    
orb2, isoform A    (B,C,D, H)
    
AAF50352.1
    
65%;80%; (3x10-143)
    
42%; 59%; (2x10-63)
  

Table 2:  Comparison of protein sequences involved in learning and memory by basic local alignment search tool (BLAST) in human (Homo sapiens), snail (Aplysia californica), and fly (Drosophila melanogaster). Abbreviations: AC: Adenylate Cyclase; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor; C/EBP: CCAAT-box-enhanced Binding Protein; CaMKII: Ca2+/Calmodulin Protein Kinase II; CaMAC: Ca2+/calmodulin-activated Adenylyl Cyclase; Ca-i-PKC: Ca2+-independent PKC; CN: Calcineurin; CPEB: Cytoplasmic Polyadenylation Element Binding Protein; DAR: Dopamine Receptor; PLC: Phospholipase C; PP1: Protein Phosphatase-1; PKA: Protein Kinase A; PKC:Protein Kinase C; NMDAR: N-methyl-D-aspartate Receptor; UH: Ubiquitin Hydroxylase; 5-HT-R: Serotonin Receptor

Close

Table 2 to 2 :

  

    
CPEB2,3,4
    
Q7Z5Q1.3 
    
CPEB
    
NP_001191467.1 
    
orb2, isoform A
      
(B,C,D,H)
    
AAF50352.1
    
39%; 57%; (2x10-53)
    
88%; 93%; (2x10-174)
  
  

    
NMDA
    
AAA21180.1
    
NMDA-typeglutamate
      
receptor 
      
precursor
    
NP_001191411.1 
    
dNR 1
    
AAF52016.1
    
56%;67%; (0.0)
    
48%; 67%; (0.0)
  
  

    
NMDA
    
AAA21180.1
    
 
    
 
    
dNR 2, isoform A
      
(B,C,D,E,F,G)
    
AAN09051.2
    
 
    
29%; 47%; (3x10-91)
  
  

    
AMPA1
      
 
    
P42261.2
      
 
    
GluR1
      
 
    
AAP41203.1 
    
glutamate receptor IA
    
AAF50652.2
    
40%; 57%; (2x10-170)
    
40%; 57%; (0.0)
  
  

    
AMPA1
    
P42261.2
    
 
    
 
    
glutamate receptor IB,
      
isoform A (B,C)
    
AAF50306.2
    
 
    
36%; 53%; (2x10-114)
  
  

    
AMPA2
      
 
    
P42262.3
      
 
    
GluR2
    
AAP41204.1
    
glutamate receptor IA
    
AAF50652.2
    
43%, 60%, (0.0)
    
42%; 58%; (0.0)
  
  

    
AMPA2
    
P42262.3
    
 
    
 
    
glutamate receptor IB
      
, isoform A (B,C)
      
 
    
AGB94317.1
    
 
    
36%; 53%; (2x10-114)
  
  

    
AMPA3
      
 
    
P42263.2
      
 
    
GluR3
    
AAP41205.1
    
glutamate receptor IA
    
AAF50652.2
      
 
    
44%; 62%; (0.0)
    
42%; 58%; (0.0)
  
  

    
AMPA3
    
P42263.2
    
 
    
 
    
glutamate receptor IB
      
, isoform A (B,C)
    
AAF50306.2
    
 
    
36%; 52%; (2x10-120)
  
  

    
AMPA4
      
 
    
P48058.2
      
 
    
GluR4
    
AAP41206.1
    
glutamate receptor IA
    
AAF50652.2
    
39%; 55%; (0.0)
    
43%; 60%; (0.0)
  
  

    
AMPA4
      
 
    
P48058.2
    
 
    
 
    
glutamate receptor IB, isoform A (B,C)
    
AAF50306.2
    
 
    
42%; 56%; (0.0)
  
  

    
5-HT-R 
    
CAA05851.1
    
5-HT-R
    
ACJ63459.1
    
5-HT-R1
    
P20905.1
    
69%;84%;(0.45)
    
83%; 100%; (1.5)
  
  

    
5-HT-R 
    
AAA66493.1
    
5-HT-R
    
ACJ63459.1
    
5-HT-R2A
    
P28285.2
    
39%; 58%; (3x10-93)
    
48%; 69%; (3x10-61)
  
  

    
5-HT-R 
    
AAA66493.1
    
 
    
 
    
5-HT-R2B
    
P28286.3
    
 
    
48%; 68%;  (3x10-62)
  
  

    
DAR D1A 
    
P21728.1
    
DAR 1-like 
    
XP_005100402.1
    
DAR
    
AAC47161.1
    
40%; 54%; (2x10-76)
    
35%; 48%; (6x10-59)
  
  

    
DAR D1B(5)
    
CAA41360.1
    
DAR1-like 
    
XP_005100402.1
    
DAR
    
AAC47161.1
    
42%; 54%, (8x101-70)
    
42%;57%; (4x10-40)
  
  

    
DARD2
    
P14416.2
    
DAR1-like 
    
XP_005100402.1
    
DAR
    
AAC47161.1
    
34%; 52%; (1x10-33)
    
34%; 49%; (1x10-62)
  
  

    
DARD3
    
P35462.2
    
DAR1-like 
    
XP_005100402.1
    
DAR
    
AAC47161.1
    
32%; 49%; (8x10-43)
    
36%; 50%; (3x10-65)
  
  

    
DARD4
    
P21917.2
    
DAR1-like 
    
XP_005100402.1
    
DAR
    
AAC47161.1
    
44%; 62%; (2x10-21)
    
40%; 54%; (8x10-26)
  
  

    
DAR D1A
    
P21728.1
    
DAR2-like 
    
XP_005099999.1
    
DAR
    
CAA54451.1
    
40%; 57%; (2x10-37)
    
40%; 55%; (6x10-71)
  
  

    
DAR D1B(5)
    
CAA41360.1
    
DAR 2-like 
    
XP_005099999.1
    
DAR
    
CAA54451.1
    
38%;53%; (8x10-36)
    
36%; 52%; (3x10-70)
  
  

    
DARD2
    
P14416.2
    
DAR 2-like 
    
XP_005099999.1
    
DAR
    
CAA54451.1
    
32%; 49%; (2x10-63)
    
36%; 56%; (2x10-35)
  
  

    
DARD3
    
P35462.2
    
DAR2-like 
    
XP_005099999.1
    
DAR
    
CAA54451.1
    
34%;49%; (1x10-58)
    
33%; 46%; (3x10-52)
  
  

    
DARD4
    
P21917.2
    
DAR2-like 
    
XP_005099999.1
    
DAR
    
CAA54451.1
    
37%;54%; (3x10-25)
    
38%; 57%; (6x10-24)
  

Table 2 to 2:  

Close

Furthermore, NMR analysis of the prion-like N-terminal domain of CPEB has shown that, apart from beta-sheet, it also has helical and random-coil structures, which are essential for enhanced binding of mRNA-binding. These results support the notion that CPEB can act as a self-sustaining prion-like protein in the nervous system [102], thereby allowing the activity-dependent change in synaptic efficacy to persist for long periods of time. Similar to Aplysia, orthologues of CPEB have been reported in Drosophila (Orb2, [103]), mice (mCPEB3, [104]), and humans (hCPEB3, [105]).

Last, but not least, Barco and co-workers went further to show that striatum-based implicit memory and hippocampus-based explicit memory (e.g., spatial memory) in mice (and probably in humans) share common molecular mechanisms [106]. However, in contrast to sensitization and classical conditioning, spatial navigation involves the formation of a cognitive map in the hippocampus and entorhinal cortex modulated by “place cells” [17,107] and “grid cells”, respectively [108]. Indeed, these cells are involved in the position, direction, and distance information for accurate spatial navigation [109]. Since the formation of spatial navigation is a learning process [110], it requires the same molecular mechanism for the consolidation of implicit and explicit long term-memory. Amazingly, the fly Drosophila melanogaster not only displays olfactory memory (implicit), but also a visual place learning [111]. Given the deep homology between the fly and mammalian brain structures and neurobiology [112-114], we anticipate that “place cells” and “grid cells” might be located in the insect central complex –e.g., ellipsoid body [111], the homolog structure of mammalian hippocampus. This assumption suggests that implicit and “explicit” memory can be recreated on the fly due to distinct neuroanatomical substrates for spatial (e.g., [115]) versus non-spatial learning (e.g., mushroom bodies are equivalent to cerebellum [116], fan-shaped body to striatum [114]. Recently, Si’s laboratory has shown a protein network comprised of protein phosphatase 2A (PP2A), Transducer of Erb-B2 (Tob), and Lim Kinase (LimK) that controls the abundance of Orb2A [117]. Indeed, the interplay between PP2A and Tob-LimK activity may dynamically regulate Orb2 amyloid-like oligomer formation and the stabilization of memories in D. melanogaster.

Together, these findings demonstrated that implicit and explicit memory processes are not restricted to vertebrates. This suggests that there might be a unified molecular mechanism for the formation of stable long-term memories and synaptic plasticity in most sub-groups of Animalia (i.e., from vertebrates (mice, humans) to molluscs (snails: A. californica) to arthropods (insects: D. melanogaster) to annelids (Caenorhabditis elegans, [118]) to handle memory encoding and retrieval. Therefore, we think that the ease of genetic manipulation in D. melanogaster [119] and its validation as a model, not only for learning and memory [120-122], but also for neurodegeneration in AD [123], provides a unique opportunity to forge an integrated mechanistic understanding of memory processing and its alterations [124].

The gray side of memory

Given that implicit and explicit memory share common molecules that are evolutionarily conserved (Table 2), [125]), what are the physiological mechanisms responsible for memory persistence in HSAM cases? What are the molecular changes that explain the early stage (pre-mild cognitive impairment or pre-clinical) in familial AD (FAD)? Can the nature of both neurologic disorders stem from similar mechanisms, but in opposite directions?

Although no data are reasonably available to answer these questions, we propose that HSAM and FAD PSEN-1 E280A [126,127] are extreme, but opposing cases of the memory process. This assumption is based on the following observations. (i) The same morphological brain structures are mostly affected in both HSAM and FAD-PSEN-1, (e.g., the medial temporal lobe). In fact, while unusual expanded regions, such as the inferior and middle temporal gyri and temporal pole, the parahippocampal gyrus, and uncinate fascicle, have been detected in HSAM individuals [61], early hippocampus and cortical atrophy have been detected in FAD patients [128]. These observations suggest that those anatomical changes represent the strength of synaptic connections in HSAM, whereas loss of neuronal synaptic connections is progressively attained in FAD. Consequently, episodic/semantic memory and cognitive functions are highly retained in HSAM [61,129], but dramatically diminished in FAD [130-134], which are detected as measurable cognitive impairment around two decades before dementia onset in PSEN1 E280A carriers [135]. (ii) Both disorders present early age at onset. In fact, onset appears at about 10 years of age in HSAM patients compared to normal individuals [60] and about 37-45 years of age in FAD (i.e., range of dementia onset in FAD compared to the mean age of MCI onset of 45 years, [50,135]). (iii) Although not yet proved in HSAM individuals, these disorders might be generated either by gene mutations (e.g., presenilin-1 in FAD [136]), up-regulation (in HSAM) and/or down-regulation (in FAD)of the PKA/CREB-1/CPEB axis [91,93,94], alterations of synaptic calcium signaling [137,138], or altered metabolism of the amyloid beta precursor protein [139], which results in the over-generation of the peptide fragment Aβ_1-42 [140] and aggregated Aβ as early as 28 years of age in asymptomatic PSEN-1 E280A mutation carriers [141]. Consequently, the molecular mechanism of consolidation and maintenance of memory at the synapse might be either up-regulated or down-regulated depending on the genetic make-up of each brain disorder.

On the understanding that oligomers of Aβ_1-42 is the primary culprit of AD/FAD [142], and that Aβ_1-42 amyloidogenesis can be initiated within living neurons rather than in the extracellular space [143-146], Aβ emerges as a molecule with a variety of cytotoxic effects. Effectively, it has been shown that Aβ is able to mediate mitochondrial toxicity [147], produce intracellular reactive oxygen species and alter calcium homeostasis [148], disrupt synaptic plasticity by altering glutamate recycling at the synapse [149], decrease spine density [150], impair the synaptic plasticity [151], and provoke neuronal loss [152] with disruption of memory-related synapse function [153]. Furthermore, Barucker and colleagues have recently shown that Aβ_1-42 might act as a regulator of gene transcription [154].

Taken together, these data suggest that, though Aβ is a multifaceted peptide that can trigger different mechanisms of toxicity, little is known about the biological activities of Aβ [155,156]. Consequently, recurrent therapeutic failure (e.g., [157]) has paved the way to cast serious doubts on its role as a principal molecule in AD [158,159]. Therefore, further alternative ways in which Aβ operates might be explored (Karran and Hardy, 2014b [157]) before dismissing the amyloid cascade hypothesis (Hardy and Higgins, 1992 [169]).

We propose an intracellular amyloid-dependent mechanism at the neuronal synapse as the cause of early onset of FAD in which Aβ directly intermingles with the CPEB. As a result of “yin-yang” prionlike protein interactions [102], Aβ might be capable of interfering with CPEB’s normal function (i.e., control of long-term synaptic plasticity and maintenance of memory consolidation), thereby triggering synaptic apoptosis [160,161]. Therefore, synapse deterioration may lead to early age onset of AD (Figure 3B). Clearly, the toxic effect of oligomer Aβ might be mediated by an intracellular mechanism (e.g., [162,163]. Our assumptions are based on the evidence that Aβ oligomers are able to interact with prion protein and provoke cellular toxicity. Indeed, Peters et al. have recently found that Aβ interacts with the PrPc, a glycosylphosphatidylinositol (GPI)-anchored membrane prion protein, which functions as a receptor of Aβ_1-42, to induce neuronal membrane damage and synaptotoxicity [164]. Dohler et al. have shown that, in Alzheimer’s disease brains, binding of Aβ to PrPc occurred via the PrPc N-terminus, which is important for proper Aβ-PrPc binding [165]. Hyeon et al. have shown that cells with abundant PrPc expression seemed to be more susceptible to Aβ_1-42 oligomer toxicity [166].

If validated, our hypothesis may help explain why anti-amyloid therapies i.e., vaccines based on anti-Aβ antibodies [167,168] have been negative or inconclusive so far [158,169,170]. Therefore, efforts should be re-directed to design therapies that target intracellular Aβ oligomers. Alternatively, studies on HSAM individuals might be invaluable to discover which molecules can be up-regulated (e.g., PKA, CREB-1, CPEB) and/or down-regulated (e.g., CREB-2, Figure 3C) to increase memory abilities in FAD. Further research is warranted to confirm or dismiss such a thesis.

Acknowledgment

This work was sponsored by CODI (project EO 1617), Universidad de Antioquia (UdeA). We thank Hector Ortega-Arellano for preparing Table 2. Alejandra Ortiz-Ramirez is acknowledged for assistance with scientific literature and fruitful academic discussions.Her participation was a partial requirement for her training under the “Young Scientists Program” at the UdeA (contract #8700-216-2013).

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Citation: Velez-Pardo C and Jimenez-Del-Rio M. From Dark to Bright to Gray Sides of Memory: In Search of its Molecular Basis & Alzheimer’s Disease. Austin J Clin Neurol 2015;2(5): 1045. ISSN : 2381-9154

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