Geon Alzheimer's Disease: The Effects of APP, Presenilin and ApoE4



Down syndrome is a genetic disorder caused by the presence of three copies of chromosome 21 where the APP gene (encoding amyloid precursor protein) is located. Down patients are prone to develop Alzheimer's disease (AD). Apolipoprotein E (ApoE) is the principal cholesterol carrier in the brain. It can have three major variants: ApoE2, ApoE3 and ApoE4. ApoE4 has been found to increase the risk for AD. Presenilin mutations are the major cause of familial AD. Earlier experimental findings appear to support the Amyloid Cascade Hypothesis which posits that AD is initiated by amyloid beta peptide (Aβ). However, recent studies have revealed new roles of APP, presenilin and ApoE4. APP plays a crucial role in normal synaptic functions. Its expression is regulated by its own intracellular domain, AICD. The extra APP gene, and thus excess AICD, in Down patients may result in neuronal hyperexcitability (Paper 7), thereby increasing the risk for AD. ApoE4 has been demonstrated to reduce the level of brain-derived neurotrophic factor (BDNF) and presenilin mutants can aggravate Ca2+ overload by stimulating IP3 receptors. These observations are consistent with the BDNF Cascade Hypothesis presented in Paper 4 and Paper 6.


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