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P4‐268: ROLE OF TAU PHOSPHORYLATION ON MICROTUBULE POLYMERIZATION
Author(s) -
Anwar Saba,
Ziu Iva,
Martic Sanela
Publication year - 2018
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.2018.07.090
Subject(s) - microtubule , microtubule polymerization , phosphorylation , tau protein , hyperphosphorylation , fyn , tubulin , microbiology and biotechnology , chemistry , microtubule associated protein , biology , biophysics , proto oncogene tyrosine protein kinase src , medicine , alzheimer's disease , disease , pathology
Background:Approximately 60% of individuals with Alzheimer’s disease (AD) have cerebrovascular pathology/mixed dementia (MD). Diabetes increases the risk for both vascular and nonvascular dementia. Less is known about prediabetes, insulin resistance and glucose intolerance in the absence of hyperglycemia. This is a critical gap in knowledge, as prediabetes is 3x more common than diabetes and affects 38% of Americans. Additionally, animal studies usingMDmodels are lacking. Moreover, since females have higher rates of dementia and faster rates of cognitive decline, sex differences must also be explored. The aim of the current study was to explore sex differences in the effects of prediabetes in mouse models of AD and MD. Methods:Male and female 3xTg-AD mice received sham (AD model) or right unilateral common carotid artery occlusion (rUCCAO) surgery (MD model) at w2.5 months of age; these were compared to wild-type (WT)/sham surgery (control) mice. Mice were then placed on low fat (LF; 10% fat) or high fat (HF; 60% fat; prediabetes model) diet for 3 months, then subjected to a glucose tolerance test, and used for either assessment of neurogenesis or behavior/cognition. Additional aspects of neuropathology (cerebral blood flow, amyloid/tau, inflammation, cell death, and integrity of white matter, vasculature, and blood brain barrier) are being assessed. Results: rUCCAO resulted in w20% reduction in blood flow to the right hemisphere immediately after surgery. HF diet increased body weight gain and visceral fat, and impaired glucose tolerance, across groups. Metabolic deficits appear to be greater in females, and in 3xTg-AD mice regardless of surgery (AD and MD models) compared to WT mice. HF diet did not affect novel object recognition performance in WT mice; however, most AD and MD groups were impaired on this task. HF diet generally impaired spatial memory in the Morris water maze across mouse models, and MD (regardless of diet) also hindered performance. Conclusions:This study will be critical for understanding sex differences in the effects of prediabetes on Alzheimer’s disease and mixed dementia, and may point to pathways that could be targeted to enhance functional outcomes.