Abstract
In Alzheimer’s disease (AD), amyloid-β peptide (Aβ) seeding leads to neuronal death through mitochondria. AD brains and most AD mouse models present a decline in neurogenesis. Mitochondria have been highlighted as a main regulator of neurogenesis. We investigated the impact of Aβ on neurogenesis via mitochondria, in a NSC line. Aβ impairs NSC viability and proliferation and indirectly blocks neurogenic differentiation, by disrupting mitochondria. Aβ decreases ATP levels whereas generates oxidative stress and reduces SOD2 and SIRT3 expression. Aβ decreases mitochondrial biogenesis markers such as mtDNA, Tfam, PGC-1α and NRF1, and promotes mitochondrial fragmentation by reducing the expression of proteins associated to mitochondrial fusion, such as Mfn2 and ERRα. However, once Aβ impairs mitochondria, NSC cell fate cannot be rescued neither through overexpressing PGC-1α, Mfn2 or Sirt3. Briefly, Aβ directly blocks viability and proliferation of NSCs, contributing for a decline of NSC pool. Moreover, Aβ irreversibly modifies mitochondrial pathways associated to mitochondrial biogenesis, dynamics and oxidative state in self-renewing NSCs, compromising neurogenic differentiation. This study warns against the use of endogenous NSCs in NSC-based therapies for AD.
Published Version
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