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

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 agedependent 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.synaptic AB | mitochondrial trafficking | mitochondrial oxidative stress | mitochondrial dysfunction | synaptic injury B rain mitochondria are a mixture of synaptic and nonsynaptic mitochondria. Synaptic mitochondria differ from nonsynaptic mitochondria in size, motility, life span, and other properties. Synaptic mitochondria are energy warehouses that sustain the activity of neurons/synapses (1, 2). Synaptic mitochondria are synthesized in neuronal soma; they are then transported to nerve terminals (dendrites and axons), are distributed abundantly around synapses where mitochondria modulate calcium balance (3), and actively provide energy to fuel the synaptic function (4, 5). Synaptic mitochondria thus undergo constant activation to maintain synaptic function. Defects in synaptic mitochondria obviously compromise synaptic function (1, 6, 7), and synaptic mitochondria are vulnerable to accumulative damages. Multiple studies have shown that synaptic mitochondria undergo increased oxidation during aging (8, 9). In addition, synaptic mitochondria demonstrate higher levels of cyclophilin D (CypD), and are thereby more susceptible to calcium insult (10, 11). Given the impor...

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

“…Our study revealed significant reductions in the number of dendritic spines in the hippocampus of 3xTg‐AD mice, suggesting that these mice have early defects in synaptic processing and neuronal communication in a brain region that is critical for learning and memory. Similar to our findings, other AD transgenic models also show reduced numbers of dendritic spines at early ages in the hippocampus, although the mechanism responsible for these dendritic spine alterations remains elusive (Chakroborty et al., 2012; Clark et al., 2015; Du et al., 2010; Jacobsen et al., 2006; Mueller et al., 2010). In addition, we also found that 3xTg‐AD mice display an increase in long immature‐type dendritic spines.…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…These changes in expression levels may be responsible for decreased mitochondrial function by causing structural abnormalities in and defective trafficking of mitochondria in HD 97 . In AD, mitochondria, especially synaptic mitochondria, show agedependent Aß accumulation 98,99 , which enhances the permeability of the mitochondrial permeability transition pore and causes the generation of reactive oxygen species 99 . Clinical trials of antioxidants that might ameliorate oxidative stress, DNA and mitochondrial damage, have not yielded conclusive results in patients with either AD or HD 100,101 .…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Decline in glucose metabolism and mitochondrial function are detected decades prior to clinical features of the disease making them potential biomarkers and therapeutic targets for prevention [12,13,24]. In vitro and in vivo preclinical AD models indicate that deficits in mitochondrial function, metabolic enzyme expression and activity, cerebral glucose metabolism, and free radical scavenging are coupled with mitochondrial Aβ load and Aβ-binding alcohol dehydrogenase (ABAD) expression [12,13,24,25]. Importantly, clinical studies indicate that mitochondrial deficits observed in preclinical models are evident in human-derived platelets [14,15,[26][27][28][29].…”