Cholesterol imbalance and neurotransmission defects in neurodegeneration

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.