Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model

TLDR

Synaptic dysfunction and loss are early hallmarks of Alzheimer’s disease, and because synapses demand high ATP and calcium handling, synaptic mitochondria are essential for transmission, yet their alteration in amyloid‑rich environments has not been extensively studied. The study aimed to compare mitochondrial properties and function between synaptic and nonsynaptic populations in a transgenic mouse overexpressing mutant APP/Aβ. Using the APP/PS1 mouse brain, the authors isolated synaptic and nonsynaptic mitochondria and assessed Aβ accumulation, respiratory function, cytochrome c oxidase activity, oxidative stress, and axonal distribution/trafficking. Synaptic mitochondria accumulated Aβ earlier and more extensively, exhibited increased permeability transition, reduced respiration and cytochrome c oxidase activity, heightened oxidative stress, and impaired axonal trafficking, indicating greater susceptibility to Aβ‑induced damage and a key role in synaptic degeneration.

Abstract

Synaptic dysfunction and the loss of synapses are early pathological features of Alzheimer's disease (AD). Synapses are sites of high energy demand and extensive calcium fluctuations; accordingly, synaptic transmission requires high levels of ATP and constant calcium fluctuation. Thus, synaptic mitochondria are vital for maintenance of synaptic function and transmission through normal mitochondrial energy metabolism, distribution and trafficking, and through synaptic calcium modulation. To date, there has been no extensive analysis of alterations in synaptic mitochondria associated with amyloid pathology in an amyloid β (Aβ)-rich milieu. Here, we identified differences in mitochondrial properties and function of synaptic vs. nonsynaptic mitochondrial populations in the transgenic mouse brain, which overexpresses the human mutant form of amyloid precursor protein and Aβ. Compared with nonsynaptic mitochondria, synaptic mitochondria showed a greater degree of age-dependent accumulation of Aβ and mitochondrial alterations. The synaptic mitochondrial pool of Aβ was detected at an age as young as 4 mo, well before the onset of nonsynaptic mitochondrial and extensive extracellular Aβ accumulation. Aβ-insulted synaptic mitochondria revealed early deficits in mitochondrial function, as shown by increased mitochondrial permeability transition, decline in both respiratory function and activity of cytochrome c oxidase, and increased mitochondrial oxidative stress. Furthermore, a low concentration of Aβ (200 nM) significantly interfered with mitochondrial distribution and trafficking in axons. These results demonstrate that synaptic mitochondria, especially Aβ-rich synaptic mitochondria, are more susceptible to Aβ-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction relevant to the development of synaptic degeneration in AD.