Figure 8. Model illustrating how PS1-E280A mutation may affect Ca²⁺ homeostasis and mitochondrial transport in cerebellar PCs.

This scheme depicts how PCs are similarly affected by Aβ in familial and sporadic AD. However, altered Ca²⁺ homeostasis due to PS1-E280A mutation promotes mitochondrial damage and impairs mitochondrial trafficking. Thus, in E280A-FAD, Aβ pathology, mitochondrial dysfunction, and abnormal levels of Ca²⁺-related proteins contribute to abnormal PC activity and cerebellar ataxia. Sequence of events may include altered Ca²⁺ ER modulation (no. 1), ER/mitochondria tethering (no. 2), mitochondrial degeneration (no. 3), and reduced mitochondrial transport (no. 4). mtPS1, mutant PS1.