HYPERTENSION INDUCES ALZHEIMER’S DISEASE-RELATED PATHOLOGIES IN MICE AND PIGS

Abstract

Middle-life hypertension (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. This study aims to test if there is a causal relationship between HTN and AD. Two animal models were used to test the role of HTN in AD pathogenesis. First, 3xTg AD model mice 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. The 3xTg mouse study: In all three ages of mice, the blood pressures were increased 7 days after the 2K1C surgery and last at least 1 month. One month after the surgery, the hippocampus-dependent memories were impaired. The levels of Aβ, amyloid precursor protein, pS412-Tau in the ventral hippocampi were elevated, while the levels of Tau protein kinase, GSK3β, were not affected. Furthermore, 7-month-old 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. The levels of Aβ, amyloid precursor protein, pT212-Tau, pS412-Tau, activated GSK3β and RAGE were increased, while the levels of LRP1 and pAKT were unchanged in the ventral hippocampi. The activities of another GSK3β upstream inhibition kinase, PKC, were decreased by AAC surgery. Immunohistochemistry revealed that the expression levels of pS412-Tau in the mossy fiber of hippocampi were increased. 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.