Hypertension increases tau hyperphosphorylation and Aβ production in 3xTg mice and pigs

Abstract

Background: Previous studies indicate an association between hypertension (HTN) and neurodegenerative disease and cognitive decline Epidemiological studies support that middle-life HTN increases the risk of late-life Alzheimer’s disease (AD) However whether HTN causes AD or is a distinct disease that increases the prevalence with age (co-morbidity) remains unclear Objective: This study aims to test if there is a causal relationship between HTN and AD Methods: Two animal models were used to test the role of HTN in AD pathogenesis First AD model mice [129-Psen1tm1Mpm Tg(APPswe tauP301L)1Lfa/Mmjax] which express three AD related mutant genes Psen1 M146V APPswe and TauP301L (hereafter 3xTg) at the ages of 2 5 and 7 months were subjected to “two-kidney-one-clip” (2K1C) surgery to induce HTN One and three months after the surgery the blood pressures hippocampus-dependent learning and memory and AD-related pathologies including Aβ production and deposition and Tau phosphorylation were evaluated Second Lanyu-miniature-pigs at the age of 7 months were subjected to abdominal aortic constriction (AAC) to induce HTN The blood pressures and AD-related pathologies were determined 1 2 and 3 months after the surgery Results: The 3xTg mouse study: The blood pressures of three ages 3xTg mice were increased 7 days after the 2K1C surgery and last at least 1 month later One month after the surgery the hippocampus-dependent non-spatial and spatial memories were impaired Furthermore the levels of Aβ amyloid precursor protein Tau phosphorylation (pS412-Tau) in the (ventral part) of hippocampi were elevated while the levels of Tau protein kinase GSK3β was not affect by 2K1C surgery In addition 7-month-old 3xTg mice subjected to 2K1C for three months showed higher amyloid plaque loads in the hippocampi than the Sham controls The pig study: Three months after the AAC surgery the blood pressures of pigs were increased Furthermore the levels of Aβ amyloid precursor protein Tau phosphorylation (pT212-Tau and pS412-Tau) GSK3β activation and receptor of advanced glycation end product (facilitation of Aβ influx from blood to brain) were increased while the levels of low-density lipoprotein receptor-related protein 1 (facilitation of Aβ efflux from brain to blood) and AKT (an upstream kinase of GSK3β) were unchanged in the ventral part of hippocampi 3 months after the AAC surgery However the activities of another GSK3β upstream inhibition kinase PKC were decreased by AAC surgery Immunohistochemistry revealed that the expression levels of Tau phosphorylation (pS412-Tau) in the mossy fiber of hippocampi were increased three months after the AAC surgery Conclusion: HTN aggravates the AD-related pathologies including impairment of hippocampus-dependent learning and memory accumulation and deposition of Aβ and increases of Tau phosphorylation Control of blood pressure during middle-life may delay the onset of AD

Date of Award	2015 Jul 21
Original language	English
Supervisor	Yu-Min Kuo (Supervisor)