Study finds that an imbalance in cholesterol may be linked to neurodegeneration, suggesting potential strategies for intervention

In a recent review published in the journal Experimental & Molecular Medicine, researchers reviewed available literature on 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).

They analyzed more than 80 publications on key mechanisms such as synaptic dysfunctions, amyloid beta (Aβ) protein oligomers, protein clustering, changes in membrane structure, and α-synuclein aggregation. Their findings indicate that changes in cholesterol synthesis and metabolism are common across most neurodegenerative diseases studied. While cholesterol-lowering drugs can somewhat reduce the risk of these diseases, further research is needed to create targeted pharmacological treatments for these conditions.

Cholesterol is a waxy, fat-like compound present in the cell membranes of all human cells. It is crucial for neuronal signaling and synaptic connections, particularly in the brain. Interestingly, the brain holds 20-25% of the body's total cholesterol reserves, making it the organ with the highest concentration of cholesterol in the human body.

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 aggregation, 3. Protein clustering, membrane structure alterations, and 4. α-synuclein aggregation.

The most essential neural protein family involved in the transport and normal metabolism of cholesterol is the apolipoprotein E (ApoE) family. ApoE4 has further been identified as a crucial risk factor in last-onset AD. Unfortunately, the molecular contributions of the ApoE family are poorly understood and require further investigation.

The mechanisms by which cholesterol affects various neurodegenerative diseases depend on the specific context. However, this study emphasises that imbalances in cholesterol levels, particularly in the brain, can elevate the risk of these diseases and proposes potential management strategies.

References: Shin, K.C., Ali Moussa, H.Y. & Park, Y. Cholesterol imbalance and neurotransmission defects in neurodegeneration. Exp Mol Med (2024), DOI – 10.1038/s12276-024-01273-4, https://www.nature.com/articles/s12276-024-01273-4