Cholesterol imbalance and neurotransmission defects in neurodegeneration

Abstract

The brain contains the highest concentration of cholesterol in the human body, which emphasizes the importance of cholesterol in brain physiology. Cholesterol is involved in neurogenesis and synaptogenesis, and age-related reductions in cholesterol levels can lead to synaptic loss and impaired synaptic plasticity, which potentially contribute to neurodegeneration. The maintenance of cholesterol homeostasis in the neuronal plasma membrane is essential for normal brain function, and imbalances in cholesterol distribution are associated with various neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. This review aims to explore the molecular and pathological mechanisms by which cholesterol imbalance can lead to neurotransmission defects and neurodegeneration, focusing on four key mechanisms: (1) synaptic dysfunction, (2) alterations in membrane structure and protein clustering, (3) oligomers of amyloid beta (Aβ) protein, and (4) α-synuclein aggregation.

Fig. 1. Schematic illustration of the roles of cholesterol in Ca²⁺-dependent vesicle fusion.

Cholesterol is essential for Ca²⁺-dependent vesicle fusion. Synaptotagmin-1, a Ca²⁺ sensor that triggers fusion, induces local deformation of the plasma membrane. The plasma membrane is normally flexible and can return to its original shape due to membrane elasticity. However, cholesterol makes the membrane less fluid and more rigid, which helps to strengthen the membrane curvature and deformation, thus lowering the energy barrier for fusion. This image was created with BioRender.com.

Fig. 2. Schematic overview of cholesterol transport to promote Aβ aggregation for neurodegeneration.

Cholesterol enhances and accelerates APP cleavage by Bace1, leading to increased Aβ oligomer and plaque formation. Cholesterol binds to Aβ and increases the resistance of Aβ fibrils and oligomers to degradation. Cholesterol imbalance and high extracellular cholesterol levels can stimulate the production and accumulation of Aβ peptides, which cause Aβ oligomer formation and aggregation in the brain, resulting in neuronal damage. This image was created with BioRender.com.