Researchers reviewed available literature on the role and mechanisms (molecular and pathological) by which cholesterol imbalances in the brain contribute to neurodegenerative disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD).
They review over 80 publications on critical mechanisms, including synaptic dysfunctions, oligomers of amyloid beta (Aβ) protein, protein clustering and membrane structure alterations, and α-synuclein aggregation. Their findings suggest that altered cholesterol synthesis and metabolism are shared features of most investigated neurodegenerative diseases. While cholesterol-lowering drugs can partially reduce these diseases' risk, additional research is required to develop future targeted pharmacological interventions against these conditions.
Study
The present study collates and reviews more than 80 publications on cholesterol to elucidate four key molecular mechanisms underpinning the associations between cholesterol imbalances and subsequent adverse neurodegenerative outcomes. These mechanisms include: 1. Synaptic dysfunction, 2. Amyloid beta (Aβ) aggregation, 3. Protein clustering, membrane structure alterations, and 4. α-synuclein (α-syn) aggregation.
Molecular Mechanisms
Synaptic dysfunction
Cholesterol has been observed to comprise up to 80% of the plasma membrane of synapses and is essential in both their formation and function. Research has highlighted that cholesterol imbalances can significantly alter the ability of synapses to share neurotransmissions effectively, eventually resulting in neurodegenerative diseases. Molecular models have revealed that cholesterol imbalances adversely impact Ca2+-dependent vesicle fusion, altering membrane elasticity. In extreme cases, this can result in significant unwanted membrane bending and curvature alterations, increasing the energy required for membrane/vesicle fusion and impairing neurotransmission.
Oligomers of Aβ protein
The amyloid precursor protein (APP) is converted into Aβ protein via enzymatic cleavage catalyzed by β-secretase Bace1. Given its integral role in protein aggregation and folding, the successful conversion of APP to Aβ protein relies on normal cholesterol levels in the brain, with alterations in the latter observed to cause misfolding in the former. Misfolding of Aβ protein results in forming Aβ plaques, the accumulation of which is a hallmark of AD pathology. "Cholesterol imbalance and elevated extracellular levels of cholesterol can promote the production and accumulation of Aβ peptides, which induce the formation of Aβ oligomers in the brain, thus contributing to neuronal damage and cognitive decline." Tau (specifically, hyperphosphorylated tau) aggregation, another hallmark of AD pathology, is also contingent on cholesterol concentrations, given the membrane curvature properties of the latter. Recent research has elucidated that cholesterol-free membranes cannot form tau fibrils, while membranes containing cholesterol influence tau fibril formation contingent on cholesterol concentration and its associated membrane curvature. Unfortunately, the impacts of cholesterol on tau nucleation remain understudied and currently unknown.
Protein clustering and membrane structure
Cholesterol has been shown to play integral roles in regulating normal membrane curvature, structure, and fluidity. Curvature and deformation are essential for vesicle function and fusion pore stabilization, enabling neurotransmitter propagation across the central nervous system. Recent research has further revealed that cholesterol is critical in the protein clustering and intracellular organization of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Communication between different SNARE proteins (syntaxin-1A, SNAP-25, and VAMP-2) together comprises the core SNARE complex, which mediates vesicle fusion and, in turn, neurotransmitter release within a synapse.
α-syn aggregation
The genesis and progression of PD are characterized by the accumulation of misfolded α-syn proteins in Lewy bodies (LBs). The mechanistic underpinnings of this process are a consequence of α-syn binding to membrane lipids. Imbalanced cholesterol accelerates α-syn aggregation and LB formation, increasing PD risk.
Conclusions
The mechanistic underpinnings of cholesterol on various neurodegenerative diseases are context-dependent. However, the present study highlights how imbalances in cholesterol levels, especially in the brain, can increase the risk of these diseases and suggests potential strategies for their management.
Source:
https://www.news-medical.net/news/20240805/Cholesterol-imbalance-linked-to-neurodegeneration-study-suggests-potential-strategies-for-intervention.aspx