From Dark to Bright to Gray Sides of Memory: In Search of its Molecular Basis & Alzheimer’s Disease

Review Article

Austin J Clin Neurol 2015;2(5): 1045.

From Dark to Bright to Gray Sides of Memory: In Search of its Molecular Basis & Alzheimer’s Disease

Carlos Velez-Pardo* and Marlene Jimenez-Del-Rio*

Neuroscience Research Group, Medical Research Institute, University of Antioquia (UdeA), Colombia

*Corresponding author: Velez-Pardo C, Neuroscience Research Group, Medical Research Institute, School of Medicine, University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412; SIU Medellin, Colombia

*Corresponding author: Jimenez-Del-Rio M, Neuroscience Research Group,Medical Research Institute, School of Medicine,University of Antioquia (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, Building 1, Room 412; SIU Medellin,Colombia

Received: March 26, 2015; Accepted: May 19, 2015; Published: May 25, 2015


Memory is one of the most fascinating functions of the brain. Without it, the human being condition would be lost. Therefore, alterations of memory are at the center of research. In this review, the most prominent memory case disorders are examined to identify basic differences and commonalities of the memory processes altered in the human brain. Then, relevant aspects of the molecular mechanism of memory between Aplysia, Drosophila, and mammals (mice) are highlighted in order to understand the biological aspect of memory in humans. The convergence of both topics provides a foundation for an integrative study of prevention and loss of memory in familial Alzheimer’s disease (FAD). Therefore, we propose that highly superior autobiographical memory (HSAM) and familial Alzheimer’s disease (FAD) are opposite extreme cases of “normal” memory and that their pathophysiology can be explained by changes in protein expression of the PKA / CREB-1 / CPEB axis. We also propose that Aβ directly intermingles with the CPEB. As a result of “yin-yang” prion-like protein interactions, Aβ is capable of interfering with the CPEB’s normal function. If validated, this hypothesis may help explain why anti-amyloid therapies have been negative or inconclusive so far. Therefore, therapies targeting intracellular Aβ oligomers are urgently needed. Molecular studies on HSAM individuals might be invaluable to discover molecules to increase memory skills in FAD.

Keywords: Alzheimer’s disease; CREB-1; CPEB; Explicit memory; Memory; HSAM; Implicit memory; Short-term memory


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-Daspartate Receptor; UH: Ubiquitin Hydroxylase; 5-HT-R: serotonin receptor


Memory is the ability of the brain to encode, store, retain, and recall information including facts, experiences, impressions, skills, and habits. It gives living things the capability to learn (i.e., the process of acquiring knowledge of the world and adapting from previous experiences to affect or influence current behavior). Etymologically, the word “memory” derives from the Latin word memory and memoir, or from the Greek word thymesis meaning “mindful” or “remembering.”Since memory is an important part of our most intimate self-realization, philosophers, medical doctors, and lately, scientists have tried to understand what memory is, how it works, and why it goes wrong. Aristotle (384 a. C.-322 a. C.) was the first to compare memory to making impressions in wax, and suggested the idea that memories are copies of reality that a person stores and later retrieves, sometimes referred to as the “storehouse metaphor,” –a theory of memory that influenced thinking for many centuries.

However, it was not until the mid-1880s that the young German psychologist Herman Ebbinghaus (1850-1909) developed the first scientific approach to studying memory. Using himself as the research subject, Ebbinghaus was able to establish the shape of the learning and forgetting curve where he discovered that early and late items in a list are more likely to be recalled than middle items (i.e., primacy and recency effects), and reported that even a small amount of initial practice, far below that required for retention, can potentially avoid the need of re-learning. Ebbinghaus also classified memory into three distinct types: sensory memory (SM, the ability to retain impressions of sensory information received through the five senses); short-term memory (STM, the capacity to hold a small amount of information in the mind in an active, readily available state for a short period of time, in the order of 20-30 seconds up to 1 min); and long-term memory (LTM, the capacity to hold an indefinite amount of information for a longer period of time, in the order of days, weeks, or years) [1]. This classification remains relevant to this day.

Furthermore, studies by George A. Miller (1920-2012) in the mid-50s demonstrated that STM is limited to what he called “the magical number seven, plus or minus two,” reflecting an STM capacity of 7 ± 2 elements [2]. By 1972, the experimental psychologist Endel Tulving (1927-present) was the first to propose two distinct types of LTM: (i) episodic, defined as the collection of past personal experiences– autobiographical events, such as time, places, associated emotions, and other contextual particulars that can be explicitly stated; and (ii) semantic, which refers to the memory of meanings, understandings, and other concept-based knowledge [3]. Both semantic and episodic memory constitutes the category of declarative memory. Declarative memory– sometimes referred to as explicit memory– refers to memories that can be consciously recalled; whereas non-declarative or procedural memory- also referred to as implicit memory- is the second category of memory in which previous experiences aid the performance of a task without conscious awareness of these previous experiences [4,5].

The most popular model for studying memory- the multi-store or modal model of memory proposed by Atkinson-Shiffrin in 1968 [6] is depicted in Figure 1A-B. This model proposes memory as a sequence of three stages, from SM to STM to LTM (blue filled arrows). The brain regions (marked in red bold) used to stack memory processes such as encoding (process by which the perceived item of interest is converted into a construct that can be stored, and then recalled later from STM to LTM), consolidation (process of stabilizing a memory trace after initial acquisition), storage (process of retaining information in either SM, STM, or LTM, but mostly in LTM), and retrieval (process of reaccessing events or information from the past previously encoded and stored) are shown in purple bold. Although the understanding of human memory has benefited from studies on animal models of dementia and cognitive dysfunction [7], several studies indicate that memory is a highly complex function of the brain for which the exact (neural and molecular) mechanisms of action remain elusive. Therefore, except for the possibility of significantly reducing aversive memory by pharmacological treatment [8], therapies or over-thecounter medicines which maintain, improve, or avoid/stop loss of memory are not currently available.