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.
View: Text | PDF
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

×

Figure 4

Mitochondrial function in hAβ-KI mice at ages 12–14 months and 20–22 months.

Options: View larger image (or click on image) Download as PowerPoint
Mitochondrial function in hAβ-KI mice at ages 12–14 months and 20–22 mon...
(A) Synaptic and nonsynaptic mitochondrial RCR of hAβ-KI and age-matched nonTg mice. One-way ANOVA followed by Bonferroni’s test (nonTg, age 12–14 months, n = 6 and age 20–22 months, n =7; hAβ-KI age 12–14 months, n = 5 and age 20–22 months, n = 6). (B) Synaptic and nonsynaptic mitochondrial CcO activity of hAβ-KI and age-matched nonTg mice. One-way ANOVA followed by Bonferroni’s test (nonTg, age 12–14 months, n = 7 and age 20–22 months n = 9; hAβ-KI, age 12–14 months, n = 5 and age 20–22 months, n = 8). (C) Synaptic and nonsynaptic mitochondrial 4-hydroxynonenal (HNE) adduct levels of hAβ-KI and age-matched nonTg mice. One-way ANOVA followed by Bonferroni’s test (nonTg, n = 7 each group; hAβ-KI, age 12–14 months, n = 5 and age 20–22 months, n = 6). (D) Synaptic and nonsynaptic mitochondrial calcium retention capacity of hAβ-KI and age-matched nonTg mice. One-way ANOVA followed by Bonferroni’s test (nonTg synaptic mitochondria, age 12–14 months, n = 6 and age 20–22 months, n = 4; nonTg nonsynaptic mitochondria, age 12–14 months, n = 6 and age 20–22 months, n = 5; hAβ-KI synaptic mitochondria, n = 5 each group; hAβ-KI nonsynaptic mitochondria, age 12–14 months n = 5 and age 20–22 months, n = 4). (E) Hippocampal basal dendritic mitochondrial volume for hAβ-KI and age-matched nonTg mice at 20–22 months old. Unpaired 2-tailed t test. n = 4 mice each group: n = 6411, 3263, 4334, and 7212 mitochondria counted in each of the 4 nonTg mice, respectively; n = 3188, 1384, 1606, and 4296 mitochondria counted in each of the 4 hAβ-KI mice, respectively. Representative images of hippocampal basal dendritic mitochondria. (E) I. Original images. Mitochondria labeled with ATP synthase α subunit (red), basal dendrites labeled with βIII-tubulin (green). II. Mitochondria (red) inside basal dendrite (gray) in the hippocampal area. Scale bars: 50 μm and 10 μm (insets). *P < 0.05; **P < 0.01; ***P < 0.001.