Abstract
Of all of the neuropathological changes observed in Alzheimer’s disease (AD), the loss of synapses correlates most strongly with cognitive decline. The precise mechanisms of synapse degeneration in AD remain unclear, although strong evidence indicates that pathological forms of both amyloid beta and tau contribute to synaptic dysfunction and loss. Synaptic mitochondria play a potentially important role in synapse degeneration in AD. Many studies in model systems indicate that amyloid beta and tau both impair mitochondrial function and impair transport of mitochondria to synapses. To date, much less is known about whether synaptic mitochondria are affected in human AD brain. Here, we used transmission electron microscopy to examine synapses and synaptic mitochondria in two cortical regions (BA41/42 and BA46) from eight AD and nine control cases. In this study, we observed 3000 synapses and find region-specific differences in synaptic mitochondria in AD cases compared to controls. In BA41/42, we observe a fourfold reduction in the proportion of presynaptic terminals that contain multiple mitochondria profiles in AD. We also observe ultrastructural changes including abnormal mitochondrial morphology, the presence of multivesicular bodies in synapses, and reduced synapse apposition length near plaques in AD. Together, our data show region-specific changes in synaptic mitochondria in AD and support the idea that the transport of mitochondria to presynaptic terminals or synaptic mitochondrial dynamics may be altered in AD.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia affecting around 30 million people worldwide
Presynaptic terminals in AD superior temporal gyrus have fewer mitochondria than controls To test the hypothesis that mitochondrial localisation in synapses is affected in AD, synapses were analysed from AD and control brain samples using transmission electron microscopy (Fig. 1)
We systematically sampled cortex to analyse synaptic mitochondria in asymmetric synapses in two brain regions, superior temporal gyrus (BA41/42) and dorsolateral prefrontal cortex (BA46). These brain regions play an important role in memory encoding and recognition (BA46) and auditory working memory (BA41/42), which are disrupted in AD [2, 58], and by the end stages of disease, both of these regions have substantial plaque and tangle pathology [54]
Summary
Alzheimer’s disease (AD) is the most common cause of dementia affecting around 30 million people worldwide. Synapse loss correlates strongly with cognitive decline in AD when measured by counting synaptic profiles with electron microscopy (EM) or by measuring synaptic protein levels [10, 11, 60]. Both Aβ and tau contribute to synapse dysfunction and degeneration in AD model systems and are observed in synapses in human AD brain [31, 40, 46, 47, 55, 63]. The causes of synapse dysfunction and degeneration in the human brain remain largely unknown. Damage to synaptic mitochondria or failure to transport enough mitochondria to synapses could both impair function and lead to synapse collapse
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