Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease
Kun Jia, … , Russell H. Swerdlow, Heng Du
Kun Jia, … , Russell H. Swerdlow, Heng Du
Published November 22, 2023
Citation Information: JCI Insight. 2023;8(22):e174290. https://doi.org/10.1172/jci.insight.174290.
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Research Article Aging Neuroscience

Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease

Abstract

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 β 42 (Aβ42) 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 Aβ (humanized Aβ-knockin [hAβ-KI] mice) confirmed the association of increased intramitochondrial sequestration of Aβ42 with exacerbated synaptic mitochondrial dysfunction in an aging factor- and AD risk–bearing context. Also, in comparison with global cerebral Aβ, intramitochondrial Aβ was relatively preserved from activated microglial phagocytosis in aged hAβ-KI mice. The most parsimonious interpretation of our results is that aging-related mitochondrial Aβ 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 Aβ, accumulation. Moreover, our findings further implicate a pivotal role of mitochondria in harboring early amyloidosis during the conversion from normal to pathological aging.

Authors

Kun Jia, Jing Tian, Tienju Wang, Lan Guo, Zhenyu Xuan, Russell H. Swerdlow, Heng Du

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Figure 3

Brain and mitochondrial Aβ in hAβ-KI mice at ages 12–14 months and 20–22 months.

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Brain and mitochondrial Aβ in hAβ-KI mice at ages 12–14 months and 20–22...
(A) Aβ40 levels in brain homogenates from hAβ-KI mice. Two-tailed t test with Welch’s correction. Age 12–14 months, n = 5; 20–22 months, n = 6. (B) Aβ42 level in brain homogenates from hAβ-KI mice. Two-tailed Mann-Whitney U test. Age 12–14 months, n = 5; 20–22 months, n = 6. (C and D) Aβ40 (C) and Aβ42 (D) levels in synaptic mitochondria from hAβ-KI mice. Unpaired 2-tailed t test. Age 12–14 months, n = 9; 20–22 months, n = 7. (E and F) Aβ40 (E) and Aβ42 (F) levels in nonsynaptic mitochondria from hAβ-KI mice. Unpaired 2-tailed t test (E) and 2-tailed t test with Welch’s correction (F). Age 12–14 months, n = 9; 20–22 months, n = 7. (G and H) Aβ oligomers in synaptic mitochondria. (G) Representative images of A11 and Tom40 dot blotting; (H) Aβ oligomers labeled by A11 Ab. Age 12–14 months: unpaired 2-tailed t test, nonTg, n = 7; hAβ-KI, n = 5. Age 20–22 months: 2-tailed t test with Welch’s correction, n = 6 each group. (I and J) Aβ oligomers in nonsynaptic mitochondria. (I) Representative images of A11 and Tom40 dot blotting; (J) Aβ oligomers labeled by A11 Ab. Unpaired 2-tailed t test. Age 12–14 months: nonTg, n = 7; hAβ-KI, n = 5. Age 20–22 months: nonTg, n =5; hAβ-KI, n = 6. *P < 0.05, **P < 0.01.