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[P3–185]: LOSS OF F‐ACTIN IN SYNAPTOSOMES CORRELATES WITH COGNITIVE DYSFUNCTION (BRAAK STAGING, B‐AMYLOID LOAD AND TANGLE LOAD) IN PATIENTS WITH MCI AND AD
Author(s) -
Ravindranath Vijayalakshmi,
Ray Ajit,
Kommaddi Reddy,
Bennett David A.
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.2017.06.1397
Subject(s) - dendritic spine , tangle , synapse , actin , pathology , alzheimer's disease , neuroscience , amyloid (mycology) , actin cytoskeleton , autopsy , cognition , biology , psychology , cytoskeleton , medicine , disease , microbiology and biotechnology , biochemistry , cell , mathematics , pure mathematics , hippocampal formation
protein that is known to define the dendritic spine morphology. It is also involved in synaptic plasticity that mediates contextual fear conditioning. The primary objective of this study was to delineate the molecular mechanisms underlying spine loss and behavioral dysfunction seen early in AD. Methods:We used APP/PS1DE9 mice (APP/PS1) and litter mate WT controls for our experiments. Contextual fear conditioning was used to assess associative fear learning and memory. We used an innovative method to isolate highly enriched F-Actin and G-Actin fractions from synaptosomes from cortices of 1, 2, 4 month old (pre-plaque phase) and 9 month old APP/PS1 mice and age matched controls. We also utilized AMS-derivatization approach to determine the reduced form of F-actin. Statistical comparisons were performed using unpaired t-tests or ANOVA followed by posthoc test. Results: We found significant decrease in F-actin levels in the synaptosomes from 1 month old APP/PS1 mice and this reduction was sustained until 9 months when overt symptoms are observed. While, F-actin levels were unaffected in post-nuclear supernatant across the ages examined. We observed loss of reduced F-actin but not reduced G-actin in the synaptosomes of APP/PS1 mice. Synaptosomal actin-Sglutathionylation, which is known to hinder F-actin polymerization, was significantly increased in 1 month old APP/PS1 mice. Interestingly the contextual fear conditioning behavioral deficits seen in APP/PS1 mice was reversed by a single intrathecal dose (500 ng/25 gram mouse) of Jasplakinolide, an actin polymerizing agent. Further, latrunculin A (500 ng/25 gram mouse), which promotes actin depolymerization induced contextual fear conditioning deficits in WT mice. Conclusions: We demonstrate that the cytoskeletal organization of F-actin is perturbed in synaptic compartment early in AD and leads to behavioral deficits, which can be reversed by actin polymerizing agents. Our results indicate that F-actin is an early target in the pathogenesis of AD.