Mitochondrial Dysfunction: A Mechanistic Link in the Progression from Normal Aging to Sporadic Alzheimer’s Disease

Synaptic mitochondria are crucial for synaptic physiology, and mitochondrial dysfunction, especially of synaptic mitochondria, has been widely recognized as a hallmark pathological feature in both normal aging and sporadic Alzheimer’s disease (AD). Aging and sporadic AD are closely linked, with aging constituting the strongest risk factor for sporadic AD. However, the question of whether synaptic mitochondrial dysfunction is the underlying mechanism driving the transition from normal aging to sporadic AD has long been debated. In this study, we report that impaired synaptic mitochondrial bioenergetics are present in amnestic mild cognitive impairment (aMCI), a transitional stage between normal aging and AD. A negative correlation between synaptic mitochondrial function and intra-synaptic amyloid beta 42 (Aβ42) levels was also observed. Additionally, by utilizing a mouse model expressing non-mutant humanized Aβ [humanized Aβ knockin (hAβ KI) mice, also referred to as a model of late-onset AD in previous literature], we identified concurrent synaptic mitochondrial deficiencies and intra-mitochondrial Aβ42 accumulation with age. Furthermore, compared to global cerebral Aβ, mitochondrial-sequestered Aβ was relatively protected from activated microglial phagocytosis in aged hAβ KI mice. Using human genome sequencing data, we identified genetic variants of mitochondrial proteins as putative causal factors for AD. Our results indicate that genetic predisposition and aging-related mitochondrial Aβ sequestration contribute to synaptic mitochondrial dysfunction during the transition from normal aging to sporadic AD.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2024

Author dc:creator

• Jia, Kun

Advisor dc:contributor.advisor

• Du, Heng

• Aging
• Neurosciences
• Alzheimer's disease
• Animal models
• Mild cognitive impairment
• Mitochondria

Language dc:language.iso

en

Dc Identifier Other

http://dissertations.umi.com/ku:19700

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/36501