Alzheimer's disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Mitochondrial dysfunction and oxidative stress are early indicators in Alzheimer's disease (AD).
• Presenilin-1 (PS1), a key component of gamma-secretase, is implicated in familial AD (FAD) when mutated and localizes to mitochondria, influencing homeostasis.

Purpose of the Study:

• To investigate the impact of five specific PS1 mutations (A431E, E280A, H163R, M146V, Δexon9) linked to FAD on mitochondrial function and homeostasis.
• To explore the role of PS1 mutations in the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) and oxidative stress.

Main Methods:

• Utilized H4 glioblastoma cell lines with inducible expression of wild-type or mutant PS1 to assess mitochondrial morphology, membrane potential, ATP production, MAMs, oxidative stress, and bioenergetics.
• Examined brains from PS1M146V knock-in mice, 3xTg-AD mice, and human AD patients to investigate PS1's role in MAMs formation.

Main Results:

• Each PS1 mutation induced distinct mitochondrial dysfunctions, including fragmentation (Δexon9) and increased MAMs formation (A431E, E280A, H163R, M146V).
• Mutations led to increased reactive oxygen species (ROS) production, impaired mitochondrial complex I and peroxidase activity (A431E, M146V), reduced membrane potential, and decreased ATP levels (A431E, M146V, Δexon9).
• PS1M146V upregulated Atlastin 2 (ATL2) in mice, increasing ER-mitochondria contacts, a phenomenon also observed in human AD brains.

Conclusions:

• The five FAD-linked PS1 mutations exert diverse detrimental effects on mitochondrial function.
• PS1 mutations contribute to MAMs formation and oxidative stress, potentially accelerating disease onset in individuals with mutant PS1.
• Elevated ATL2 expression is linked to increased ER-mitochondria interactions in PS1-mutated models and human AD, suggesting a role in disease pathogenesis.