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P3‐194: TRANSCRIPTOMIC PROFILING OF TAUOPATHY REVEALS GENE POPULATIONS RESPONSIVE TO TAU EXPRESSION AND A SUBPOPULATION OF THERAPEUTICALLY RELEVANT GENES
Author(s) -
Koren Shon,
Nation Grant K.,
Meier Shelby E.,
Chishti Emad,
Blalock Eric,
Abisambra Joe F.
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.2018.06.1552
Subject(s) - tauopathy , transcriptome , biology , transgene , microbiology and biotechnology , microarray , neurodegeneration , gene expression , gene , doxycycline , gene expression profiling , microarray analysis techniques , tau protein , dna microarray , fold change , genetics , pathology , disease , alzheimer's disease , medicine , antibiotics
Background:Metformin is used for the treatment of insulin resistant diabetes. Diabetics are at an increased risk of developing dementia and insulin resistance in the CNS has been found in Alzheimer’s disease (AD). Recent epidemiological studies suggest in diabetics that metformin treatment prevents cognitive decline. A pilot clinical study found cognitive improvement with metformin in patients with MCI. Preclinical studies have found that metformin increases PKC, a regulator of the Ab and Tau pathways. In addition, studies have found that metformin reduces AD-like pathology in mouse models of AD. The SAMP8 mouse is a model of spontaneous onset of AD. The SAMP8 mice have age-related impairment in learning and memory that correlates with an elevation of amyloid precursor protein (APP), amyloid beta (Ab), and hyperphosphorylated tau (pTau). Methods: In the current study, we used 11 month old SAMP8 mice. Mice were given daily injections of metformin at 20mg/kg or 200mg/kg for 8 weeks. After 4 weeks mice were tested in T-maze foot shock avoidance, object recognition and Barnes maze. At the end of the study brain tissue was collected for analysis of mitochondrial BAX, PKCz, PKCi, PKCa, PKCb, PKCg, PKCε,GSK-3b, pGSK-3Bser9, pGSK-3btyr216, pTau404 and APP analysis. Results:Metformin improved both acquisition and retention in SAMP8 mice in T-maze foot shock avoidance, retention in novel object recognition and acquisition in the Barnes maze. Biochemical analysis indicated that metformin decreased mitochondrial BAX, increased both atypical and conventional forms of PKC; PKCz, and PKCa at 20 mg/kg (P<0.05 and P<0.01 respectively). Metformin significantly increased pGSK3bser9 at 200mg/kg (P<0.05), and decreased pTau404 (P<0.05) and APPc99 (P<0.001) at both 20mg/kg and 200mg/kg. There was no difference in blood glucose levels between the aged vehicle treated mice and the mice that received metformin. Conclusions: Metformin improved learning and memory in the SAMP8 mouse model of spontaneous onset AD. Biochemical analysis indicates that metformin improve memory by increasing PKC which lead to alterations in pGSK-3b which decreases pTau and APP. The current study lends support to the therapeutic potential of metformin for AD.