In a recent review published in the journal Experimental & Molecular Medicine, researchers meticulously examined existing literature to uncover the role and mechanisms 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).
The review analyzed over 80 publications, shedding light on critical mechanisms including synaptic dysfunctions, oligomers of amyloid beta (Aβ) protein, protein clustering and membrane structure alterations, and α-synuclein aggregation.
The findings suggest that altered cholesterol synthesis and metabolism are shared features among most neurodegenerative diseases. While cholesterol-lowering drugs can partially mitigate the risk of these conditions, additional research is necessary to develop targeted pharmacological interventions.
Background
Cholesterol, a waxy, fat-like substance, is a vital component of cell membranes throughout the human body. It plays a crucial role in neuronal signaling and synaptic connections, particularly in the brain, which contains between 20-25% of the body’s total cholesterol reserves.
Unlike peripheral cholesterol absorbed from the diet and circulating in the bloodstream, brain cholesterol cannot cross the blood-brain (BBB). Hence, nearly all brain cholesterol is synthesized in situ by glial cells and neurons.
As humans age, the efficiency of cholesterol synthesis in glia and neurons diminishes, reducing brain cholesterol reserves. This reduction impairs synaptic plasticity and leads to overall synaptic loss, contributing significantly to the risk of neurodegenerative diseases such as AD, HD, and PD. However, the molecular and pathological mechanisms behind these observations remain underexplored.
The Study
The current review collated and analyzed more than 80 publications to elucidate four key molecular mechanisms that connect cholesterol imbalances to adverse neurodegenerative outcomes. These mechanisms include:
- Synaptic dysfunction
- Amyloid beta (Aβ) aggregation
- Protein clustering and membrane structure alterations
- α-synuclein aggregation (α-syn) aggregation
Molecular Mechanisms
- Synaptic Dysfunction
Cholesterol constitutes up to 80% of the plasma membrane of synapses, essential for their formation and function. Research indicates that cholesterol imbalances can significantly impair synaptic efficiency, leading to neurodegenerative diseases. Molecular models have shown that cholesterol imbalances disrupt Ca2+dependent vesicle fusion and alter membrane elasticity. In extreme cases, this can cause significant 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 by β-secretase Bacel. This process relies on normal cholesterol levels in the brain. Altered cholesterol levels can cause APP misfolding, resulting in Aβ plaque formation, 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.”
Hyperphosphorylated tau aggregation, another AD hallmark, is also influenced by cholesterol concentrations. Cholesterol-free membranes cannot form tau fibrils, whereas cholesterol-containing membranes influence tau fibril formation based on cholesterol concentration and membrane curvature. However, the impacts of cholesterol on tau nucleation remain understudied.
- Protein Clustering and Membrane Structure
Cholesterol regulates normal membrane curvature, structure, and fluidity, essential for vesicle function and fusion pore stabilization, enabling neurotransmitter propagation across the central nervous system. Recent research has shown that cholesterol is critical in the protein clustering and intracellular organization of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. The communication between different SNARE proteins (syntaxin-1 A, SNAP-25, and VAMP-2) comprises the core SNARE complex, mediating vesicle fusion and neurotransmitter release within a synapse.
- α-synuclein aggregation
The progression of PD is characterized by the accumulation of misfolded α-syn proteins in Lewy bodies (LBs). This process results from α-syn binding to membrane lipids, with imbalanced cholesterol accelerating α-syn aggregation and LB formation, thereby increasing PD risk.
Future Therapeutic Interventions
The apolipoprotein E (ApoE) family (ApoE2, ApoE3, and ApoE4) plays a vital role in cholesterol transport and metabolism in the brain. ApoE4, in particular, is a significant risk factor for late-onset AD. Despite its importance, the molecular contributions of the ApoE family are poorly understood and require further investigation. Given the role of ApoE4 in both cholesterol homeostasis and AD pathology, it stands out as a potential target for clinical trials and future pharmacological interventions.
Conclusions
The mechanistic underpinnings of cholesterol’s impact on various neurodegenerative diseases are complex and context-dependent. However, this review highlights that cholesterol imbalances, particularly in the brain, can increase the risk of these diseases.
The findings suggest potential strategies for managing neurodegenerative conditions through targeted research and therapeutic interventions. As the understanding of cholesterol’s role in brain health deepens, it opens the door to innovative approaches in combating debilitating neurodegenerative diseases.
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