Pathophysiology of Hypertension: Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease

there is growing epidemiological evidence that hypertension increases the risk (risk ratio = ∼1.5) for sporadic Alzheimer's disease (AD), the most common cause of dementia in the elderly (23, 27). The amyloid cascade hypothesis remains the most frequently invoked hypothesis to explain the cause of AD. It posits that altered production and/or processing of amyloid-β peptides, derived from amyloid precursor protein (APP), play a central role in the development of AD, a concept that is supported by substantial genetic and biochemical data. Yet, despite the old concept that the pathomechanisms of AD and vascular cognitive impairment are inherently different, recent clinical and experimental studies strongly suggest that cerebromicrovascular impairment plays a key role in the pathogenesis of AD as well (18, 21, 26, 47). As predicted by the vascular hypothesis of AD (60), many vascular risk factors, including hypertension, increase the probability to develop AD in the elderly. Although there are studies extant investigating the possible vascular mechanisms underlying the cognitive decline induced by hypertension (9, 20, 30), the pathophysiological mechanistic links among hypertension, Aβ peptides, and the development of AD still remain elusive. Recent experimental studies give further support for both the amyloid cascade hypothesis and the vascular hypothesis of AD by demonstrating that hypertension in mice (induced by transverse aortic coarctation) promotes Aβ-deposition, which associates with cognitive decline (10–12). Importantly, in mice brain Aβ deposits are detectable as early as 4 wk after induction of hypertension (10–12), suggesting that hypertension-induced cerebromicrovascular impairment is sufficient to trigger molecular processes leading to AD. The aforementioned studies implicate oxidative stress and neuroinflammation in the development of AD-like pathologies in hypertensive mice (10–12). Despite these advances, the cellular and molecular mechanisms by which hypertension affect neuronal function and phenotype in the brain are not well understood. Importantly, there are no studies extant characterizing the effect of hypertension on the neuronal gene expression. Aging is the single most important risk factor for AD, but the interaction between aging and hypertension in the genesis of AD has not been understood. Our recent studies provide important evidence that aging exacerbates hypertension-induced cognitive decline and neuroinflammation (50), likely because of the increased vulnerability of the aged cerebral microcirculation to the deleterious effects of hypertension. On the basis of these findings and recent data showing that neuroinflammation contribute to cognitive decline in hypertension (11), we predict that aging may exacerbate hypertension-induced alterations in hippocampal expression of AD-related genes. The present study was designed to characterize the additive/synergistic effects of hypertension and aging on the expression of genes involved in β-amyloid generation and AD in the hippocampus, an area of brain contributing to higher cognitive function, which is significantly affected by AD both in humans and in mouse models of the disease. To achieve that goal, we induced hypertension in young and aged C57BL/6 mice by chronic infusion of angiotensin II (ANG II) followed by tests for learning and spatial memory and assessment of changes in hippocampal expression of relevant genes.