Highlights d Ab and tau work together to cause behavioral and transcriptional deficits in mice d In mice with Ab and tau, glial gene expression increases and synaptic genes decrease d Tau is present in synaptic terminals in APP/PS1+Tau mice and human Alzheimer brain d In mice, lowering tau levels improves cognition and restores gene expression

Synaptic proteomes have evolved a rich and complex diversity to allow the exquisite control of neuronal communication and information transfer. It is therefore not surprising that many neurological disorders are associated with alterations in synaptic function. As technology has advanced, our ability to study the anatomical and physiological function of synapses in greater detail has revealed a critical role for both central and peripheral synapses in neurodegenerative disease. Synapse loss has a devastating effect on cellular communication, leading to wide ranging effects such as network disruption within central neural systems and muscle wastage in the periphery. These devastating effects link synaptic pathology to a diverse range of neurological disorders, spanning Alzheimer's disease to multiple sclerosis. This review will highlight some of the current literature on synaptic integrity in animal models of disease and human post-mortem studies. Synaptic changes in normal brain ageing will also be discussed and finally the current and prospective treatments for neurodegenerative disorders will be summarised.

Alzheimer's disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-β (Aβ) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aβ associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aβ and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aβ oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aβ inside synaptic terminals. Further, we tested a panel of Aβ antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aβ species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue.

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.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1903-2) contains supplementary material, which is available to authorized users.