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[P3–183]: SELECTIVE DEGENERATION OF ENTORHINAL‐CA1 SYNAPSES IN ALZHEIMER's DISEASE VIA ACTIVATION OF DAPK1
Author(s) -
Pang Pei
Publication year - 2017
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 - 10.1016/j.jalz.2017.06.1395
Subject(s) - inhibitory postsynaptic potential , neuroscience , excitatory postsynaptic potential , degeneration (medical) , entorhinal cortex , parvalbumin , biology , hippocampus , medicine , pathology
against the AbO cSNK epitope was evaluated by surface plasmon resonance (SPR), dot blotting/immunoblotting, immunoprecipitation, immunohistochemistry and immunoelectron microscopy. The percent of AbO falling into the cSNK subclass was defined by acute peripheral infusion of antiAbO in aged animals of two AD mouse models (Tg2576 and APP/PS1) followed by soluble Ab aggregate quantification. Behavioural toxicity of AbO was evaluated in vivo by: 1) AbO intraventricularly co-injected with the antiAbO antibody into C57BL/6 wild-type mice followed by Novel Object Recognition testing, and 2) Chronic cSNK peptide immunization of APP/PS1 mice starting at 3 months of age and continuing monthly until sacrifice at 12 months, with Cued and Contextual Fear Conditioning testing at 11 months. Immunobloting and immunohistochemistry identifed AbO sensitive cells and brain regions. Results: A mouse monoclonal antibody targeting AbO recognizes w50-60 kDa SDS-resistant Ab soluble assemblages in AD brain. Acute peripheral infusion of anti-AbO in AD mouse models reduced soluble brain Ab aggregates by 20-30%. Chronic cSNK peptide immunization of APP/PS1 mice generated an anti-AbO IgG1 response without epitope spreading to Ab monomers or fibrils, and was accompanied by preservation of global PSD95 expression and improved cued fear memory. The anti-AbO IgG1 reduced amygdalar plaque burdens in female mice, with no effect on hippocampal plaque. Conclusions: A parsimonious interpretation of the results is that antibodyaccessible brain AbO, a minority of total AbO, participate in AD synaptic architectural disruption, with specific toxicity for post-synaptic dendrites, and seeding of Ab fibrillogensis via the hippocampal-amygdala connectome. The IgG1 response indicates local neutralization/clearance, without the participation of Fc receptor-bearing cells. We demonstrate that pathogenic activities of AbO subclasses can be defined in vivo by immunological subtraction.