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Synapse disruption by Alzheimer’s Aβ/APP
Author(s) -
Gouras Gunnar K.,
Martinsson Isak
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043447
Subject(s) - neuroscience , synapse , calcium imaging , biology , excitatory postsynaptic potential , genetically modified mouse , hippocampal formation , inhibitory postsynaptic potential , soma , live cell imaging , senile plaques , neuron , microbiology and biotechnology , transgene , alzheimer's disease , calcium , cell , chemistry , pathology , medicine , biochemistry , genetics , disease , organic chemistry , gene
Background Synapse loss is known as the best brain correlate of cognitive decline in AD, while numerous lines of evidence support that Aβ/APP are involved in the disease. We previously reported that with AD pathogenesis soluble Aβ42 accumulates in late endosomes near synaptic terminals where it then aggregates and disrupts synapses. Based on these studies our modified amyloid hypothesis views intra‐neuritic Aβ as initiating a cascade that after synaptic degeneration via prion‐like extracellular Aβ propagation perpetuates the pathological process. This scenario illuminates the Aβ‐tau anatomical disconnect, since vulnerable projection neurons with early Aβ accumulation later develop tangles at their cell soma but plaques in their terminal fields. Here we set out to better understand the effects of early Aβ accumulation on synapses using live cell calcium imaging in cultured primary neurons. Method Primary cortical/hippocampal neurons are obtained from APP/PS1 mutant transgenic and wild‐type mice. We previously reported that primary AD transgenic neurons show progressive Aβ accumulation and AD‐like synapse alterations. After live cell calcium imaging of neurons with Fluo‐4, neurons are fixed and immuno‐labeled with markers for inhibitory or excitatory cells. In addition, viral constructs harboring fluorescent tags (e.g. TdTomato) and promoters to label excitatory or inhibitory neurons are used to measure calcium oscillations directly in different types of neurons during live imaging. Result By live cell imaging primary neurons from AD transgenic compared to wild‐type mice showed hyperactivity consistent with prior in vivo work. Calcium oscillations were increased in both frequency and amplitude in the AD transgenic neurons. Conclusion Synapses are increasingly viewed as vulnerable early sites in AD. Here we show evidence for neuronal hyperactivity related to Aβ/APP and aim to dissect the neuron subtype vulnerability of these early Aβ‐induced synaptic alterations.