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P1‐162: SUPPRESSIVE EFFECTS OF AMYLOID PEPTIDE FRAGMENTS ON MACRO‐ AND MICRO‐SCOPIC KV1.1 CHANNEL ACTIVITY
Author(s) -
DeBoeuf Kristi,
Islam Mohammad F.,
Thelen Nick S.,
Farley Joseph
Publication year - 2019
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.2019.06.717
Subject(s) - xenopus , long term potentiation , biophysics , chemistry , patch clamp , depolarization , peptide , membrane potential , voltage clamp , western blot , electrophysiology , pharmacology , microbiology and biotechnology , medicine , endocrinology , neuroscience , biology , biochemistry , receptor , gene
Background: Previously, we have identified characteristic signs of Alzheimer’s disease (AD) in the retina, a developmental outgrowth of the brain, presented as amyloid b-protein (Ab) deposits. We further demonstrated the feasibility of non-invasive detection of amyloid deposits in the retina and similar reduction of cerebral and retinal Ab plaques in response to immunomodulation in young-adult APPSWE/PS1DE9 (ADtg) mice. However, the exact relationship between retinal and brain Ab pathology and effects of GA immunomodulation in old mice, argued to better correspond to the clinical human disease, have not been previously investigated. Methods: Here, we measured amyloidogenic and non-amyloidogenic Ab peptide concentrations in both retinal and brain tissues of aged, late-stage (21-24 months) ADtg mice and response to GA immunotherapy. Sensitive biochemical MSD assays as well as immunohistochemistry and mass spectrometry were applied to assess and quantify the changes in Ab burden, astrocytosis and synaptic biomarkers within retinal and brain tissues. Results: Our data indicates strong and direct correlations between cerebral and retinal levels of amyloidogenic Ab40 and Ab42 peptides, even at a late disease stage. Similar responses to GA immunotherapy were also recorded in these CNS tissues. Therapeutic effects of GA on Ab burden were mostly localized to the entorhinal cortices. Additional assessment of cerebral plaque phenotype revealed a targeted response to large sized plaques, determined by their area, length and width, and dense-core Ab aggregates. Importantly, GFAP astrocytosis was restricted following GA immunization in all analyzed brain regions (hippocampus, cingulate cortex and entorhinal cortex). In-depth analysis of astrocyte morphology and functional biomarkers showed a restoration of homeostatic levels of glutamine synthetase (GS), an astrocyte-associated enzyme involved in extracellular synaptic glutamate recycling, following GA immunizations. Further, analysis of synaptic density in these aged mice indicated enhanced postsynaptic PSD95 biomarker expression following GA immunization in areas of reduced Ab pathology. Conclusions: Our results illustrate the efficacy of immune-intervention, even at late disease stages, and portray the first quantifiable method for retinal Ab determination, further emphasizing the potential of the retina as a predictive biomarker for cerebral AD.