"" Diabetes and Cholesterol Dyshomeostasis Involve Abnormal α-Synuclein and Amyloid Beta Transport in Neurodegenerative Diseases

Review Article

Austin Alzheimers J Parkinsons Dis. 2015;2(1): 1020.

Diabetes and Cholesterol Dyshomeostasis Involve Abnormal α-Synuclein and Amyloid Beta Transport in Neurodegenerative Diseases

Martins IJ1,2,3*

¹Centre of Excellence in Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Australia

²School of Psychiatry and Clinical Neurosciences,University of Western Australia, Australia

³McCusker Alzheimer's Research Foundation, Holywood Medical Centre, Australia

*Corresponding author: Ian J Martins, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, Western Australia 6027,Australia.

Received: December 14, 2014; Accepted: July 16, 2015;Published: July 18, 2015

Abstract

The understanding of molecular mechanisms underlying diet and Alzheimer's disease and the cholesterol connection are important for the prevention and treatment of Alzheimer's disease linked to Type 3 diabetes and aberrant lipid metabolism. Cholesterol modulates amyloid beta generation with the ATP-binding cassette transporter 1 as a major regulator of cholesterol and phospholipids from cell membranes that are involved in amyloid beta transport from the brain to the liver for metabolism. In Parkinson's disease, the α-synuclein protein binds to cholesterol (tilted peptide 67-78/isooctyl chain) in cell membranes. Fatty acids and phospholipids such as phosphatidylinositol in membranes sensitive to amyloid beta and α-synuclein binding/aggregation indicate the involvement of lipids in the progression of Alzheimer's disease. Atherogenic diets with abnormal cell cholesterol homeostasis exist as a cellular mechanism, which is common to the aggregation of amyloid beta and α-synuclein proteins that induce both Alzheimer's disease and Parkinson's disease. Sirtuin 1,a nuclear receptor known to regulate cell functions by deacetylating both histone and non-histone targets when down regulated is associated with circadian abnormalities and with poor glucose and cholesterol metabolism linked to abnormal amyloid beta metabolism in Alzheimer's disease and increased α-synuclein aggregation in Parkinson's disease. The global obesity and Type 2 diabetes epidemic indicate that the down regulation of Sirtuin 1 with increased inflammatory processes and abnormal immune responses associated with increased plasma α-synuclein levels, has become important for the modulation of membrane ion channels and impairments in protein degradation with abnormal endoplasmic reticulummitochondrial interactions associated with disturbed peripheral amyloid beta metabolism common to both Parkinson's disease and Alzheimer's disease.

Keywords: α-synuclein; Amyloid beta; Cholesterol; Ceramide; Sirtuin 1; Lipopolysaccharide

Abbreviations

PD: Parkinson's Disease; AD: Alzheimer's Disease; apoE: Apolipoprotein E; ABCA1: ATP-binding Cassette Transporter 1; Aβ: Amyloid Beta; APP: Amyloid Precursor Protein; Sirt1: Sirtuin1; LXR: Liver X Receptor; PPAR: Peroxisome-proliferator-activated Receptor; PGC 1 alpha: PPAR Gamma co-activator 1 α; SREBP; Sterol Regulatory element-binding proteins; LPS: Lipopolysaccharide; HDL: High Density Lipoprotein

Introduction

The main constituent of senile plaques, namely amyloid beta (Aβ) [1], is a proteolytic product of a larger protein, the amyloid precursor protein (APP). The main protein component of Alzheimer's disease (AD) senile plaques, Aβ, was firstly purified and sequenced from cerebrovascular amyloid deposits which manifest as congophillic amyloid angiopathy [2]. Aβare found to be peptides of 39 to 43 amino acids in length, with an approximate molecular mass of 4.2 kDa [2]. Another study published from the same research group has linked Aβ to adult Down's syndrome and AD [3]. The understanding of molecular mechanisms underlying the AD-cholesterol connection has become important for the possible prevention and treatment of AD and it is now linked to diabetes and poor cholesterol metabolism. Plasma cholesterol profiles such as elevated low density lipoprotein and decreased high density lipoprotein (HDL) levels have been associated with AD and are important risk factors for cardiovascular diseases. Furthermore, diets that are rich in fat and cholesterol have been associated with brain amyloidosis in rabbits and AD transgenic mice. Diabetes and dyslipidemia are linked to amyloidosis with relevance to calcium dyshomeostasis and neurodegenerative diseases [4]. Cholesterol modulates APP processing and Aβ generation with the action of 3 proteases [5-7]. Depletion of cholesterol and inhibition of intracellular transport of cholesterol or cholesterol esterification by drugs inhibited the production of Aβ formation in hippocampal neurons [8-13]. Studies indicate that cholesteryl ester (CE) levels are correlated with Aβ levels, and that cholesterol lowering drugs such as ACAT inhibitors directly modulate Aβ generation through the control of CE generation [14]. The ATP-binding cassette transporter 1 (ABCA1) is a major regulator of HDL with the transport of cholesterol and phospholipids from cell membranes to HDL possibly plays a central role in cholesterol flux and Aβtransport from the CNS to the periphery where it is transported to the liver for metabolism and subsequent excretion [15]. High fat and cholesterol diets may induce both AD and PD with the indications that abnormal cholesterol homeostasis exists as the cellular mechanisms that are common to the aggregation of Aβ and α-synuclein proteins [15-17]. In PD, the movement disorder is characterized by the aggregation of α-synuclein protein (14 kda) in Lewy body inclusions with dopaminergic neuron apoptosis in the substantia-nigra [18,19]. Epidemiological studies indicate that Type 2 diabetes and PD are closely linked with shared dysregulated pathways that involve molecular genetics, cell biology and insulin resistance in the pathogenesis of these diseases [20.21]. In Parkinson's disease, the α-synuclein protein is an amyloidogenic protein and has been shown to bind to cholesterol (tilted peptide 67- 78) and α-synuclein has also been shown with binding to the isooctyl chain of cholesterol in membranes [22,23]. In recent publications, the binding of Aβ has been associated with cholesterol in membranes with the regulation of liver Aβ metabolism regulated by lipoprotein cholesterol levels [15]. The peripheral sink abeta hypothesis [16] is closely associated with cholesterol regulation and possibly connected to the metabolism of Aβ and α-synuclein proteins in diabetes, AD, PD and Huntington's disease. In diabetes, circadian clock abnormalities [24] are central to disease progression and circadian disturbances are also found in neurodegenerative disease that involves AD and PD [25-28]. Regulation of the peripheral Aβ clearance is central to the disease of diabetes with circadian clock abnormalities now believed to be the origin of poor liver glucose, cholesterol and Aβ metabolism in diabetes [16]. Neurons in the hypothalamus are responsible for various connections to other brain regions and one of the important functions of the hypothalamus is control of the daily light dark cycle. The suprachiasmatic nucleus (SCN) may regulate the sleepwake cycle and peripheral oscillators with effects on anxiety, stress, depression and food intake. In response to the daily sleep/wake cycle Aβ metabolism, α-synuclein metabolism is controlled by the circadian rhythm, SCN [29-32] with relevance to food intake and release of pineal gland melatonin. Disturbances in the SCN will alter energy and liver glucose and Aβ metabolism with hyperglycemia closely involved with abnormal resetting of circadian rhythms and melatonin release.

Sirt 1 and insulin resistance involve circadian dysregulation with connections to membrane lipids and protein aggregation

Sirtuin 1 (Sirt1) is one of the nuclear receptors that is known to regulate several cell functions by deacetylating both histone and nonhistone targets [33]. Sirt1 is an NAD(+)dependent class III histone deacetylase protein that targets transcription factors to adapt gene expression to metabolic activity, insulin resistance and inflammation in chronic diseases [34-38]. Nutritional regulation (calorie restriction and high fat feeding) of Sirt1 that is involved in the hypothalamic and SCN control of food intake with regulation of the central melanocortin system via the fork head transcription factor has been reported [39-42]. Sirt1 dysregulation has been closely linked with alterations in appetite regulation and with circadian clock disorders that are associated with obesity and diabetes. In support of Sirt1's role in circadian rhythms [43-47] subjects carrying minor alleles at Sirt1 and CLOCK loci, displayed a higher resistance to weight loss as compared with homozygotes for both major alleles, suggesting links between the circadian clock and Sirt1 function. Sirt1 is involved in neuron proliferation with effects on cellular cholesterol and lipid homeostasis by the regulation of liver X receptor (LXR) proteins. Sirt1 has been closely linked to Aβ metabolism in AD (Figure 1) and α-synuclein metabolism in PD with circadian dysregulation that is associated with protein aggregation [29-32] and with implications to Sirt1 research and therapeutics in Huntington's disease [48].

Citation: Chaudhry ZL and Ahmed BY. The Role of Caspases in Parkinson’s Disease Pathogenesis: A Brief Look at the Mitochondrial Pathway. Austin Alzheimers J Parkinsons Dis. 2014;1(4): 5. ISSN: 2377-357X