| First Author | Jia K | Year | 2023 |
| Journal | JCI Insight | Volume | 8 |
| Issue | 22 | PubMed ID | 37991017 |
| Mgi Jnum | J:343613 | Mgi Id | MGI:7566701 |
| Doi | 10.1172/jci.insight.174290 | Citation | Jia K, et al. (2023) Mitochondria-sequestered Abeta renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease. JCI Insight 8(22) |
| abstractText | Mitochondria are critical for neurophysiology, and mitochondrial dysfunction constitutes a characteristic pathology in both brain aging and Alzheimer disease (AD). Whether mitochondrial deficiency in brain aging and AD is mechanistically linked, however, remains controversial. We report a correlation between intrasynaptosomal amyloid beta 42 (Abeta42) and synaptic mitochondrial bioenergetics inefficiency in both aging and amnestic mild cognitive impairment, a transitional stage between normal aging and AD. Experiments using a mouse model expressing nonmutant humanized Abeta (humanized Abeta-knockin [hAbeta-KI] mice) confirmed the association of increased intramitochondrial sequestration of Abeta42 with exacerbated synaptic mitochondrial dysfunction in an aging factor- and AD risk-bearing context. Also, in comparison with global cerebral Abeta, intramitochondrial Abeta was relatively preserved from activated microglial phagocytosis in aged hAbeta-KI mice. The most parsimonious interpretation of our results is that aging-related mitochondrial Abeta sequestration renders synaptic mitochondrial dysfunction in the transitional stage between normal aging and AD. Mitochondrial dysfunction in both brain aging and the prodromal stage of AD may follow a continuous transition in response to escalated intraneuronal, especially intramitochondrial Abeta, accumulation. Moreover, our findings further implicate a pivotal role of mitochondria in harboring early amyloidosis during the conversion from normal to pathological aging. |
