Angiotensin Receptor Blocker Prevented β-Amyloid-Induced Cognitive Impairment Associated With Recovery of Neurovascular Coupling

Abstract

Abstract-Recent studies suggest that vascular risk factors play a considerable role in the development of Alzheimer disease. Furthermore, the use of antihypertensive drugs has been suggested to reduce the incidence of dementia, including Alzheimer disease. In this study, we examined the effects of an angiotensin receptor blocker, olmesartan, on ␤-amyloid-induced cerebrovascular dysfunction and cognitive impairment. Oral administration of a low dose of olmesartan attenuated cerebrovascular dysfunction in young Alzheimer disease-model transgenic mice (APP23 mouse), without a reduction in the brain ␤-amyloid level. Moreover, treatment of APP23 mice with olmesartan decreased oxidative stress in brain microvessels. Using an acute mouse model induced by ICV administration of ␤-amyloid 1-40, we assessed the effect of oral administration of olmesartan on spatial learning evaluated with the Morris water maze.Olmesartan significantly improved cognitive function independent of its blood pressure-lowering effect, whereas there was no improvement by other types of antihypertensive drugs (hydralazine and nifedipine). We found that pretreatment with a low dose of olmesartan completely prevented ␤-amyloid-induced vascular dysregulation and partially attenuated the impairment of hippocampal synaptic plasticity. These findings suggest the possibility that amelioration of cerebrovascular dysfunction with an angiotensin receptor blocker could be a novel therapeutic strategy for the early stage of Alzheimer disease. Key Words: angiotensin receptor blocker Ⅲ hypertension Ⅲ renin-angiotensin system Ⅲ dementia Ⅲ Alzheimer disease A lzheimer disease (AD) is the most common form of dementia. One of the major neuropathological hallmarks of AD is accumulation of ␤-amyloid peptide (A␤) in the brain. 1 A␤ is a 38-to 43-amino acid peptide produced from amyloid precursor protein (APP) by proteolytic processing. Abnormal accumulation of A␤-peptide in the brain is associated with a cascade of pathological events, resulting in dementia. 1 Recently, alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of the early stage of AD. [2][3][4] The strategy for AD treatment is shifting to earlier stage intervention or prevention of this disease. Amelioration of cerebrovascular dysregulation could be a novel therapeutic target.Importantly, there is a growing body of evidence indicating an association between vascular risk factors and AD. 5 Several epidemiological studies have shown that hypertension in midlife is related to the development of AD. 5,6 Furthermore, some antihypertensive drugs reduce the incidence of dementia, including AD. For example, in the Systolic Hypertension in Europe Study, active therapy with a calcium channel blocker, nitrendipine, reduced the incidence of AD. 7 The Cache County Study of Memory and Aging concluded that the use of antihypertensive medication is associated with a lower incidence of AD. 8 On the other hand, previous studies have revealed contributory ...

High plasma aldosterone concentration is a novel risk factor of cognitive impairment in patients with hypertension

“…[16][17][18][19][20][21] In addition, as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and potassium sparing diuretics have an advantage in preventing CI, activation of the renin-angiotensin system or low potassium concentration has been suggested to be involved in CI through possible contributors to CI pathogenesis, including oxidative stress, inflammation, platelet aggregation and vasoconstriction. [22][23][24][25][26][27][28][29] Aldosterone, a crucial factor downstream of the renin-angiotensinaldosterone system, has also been shown to cause target organ damage independent of its effects on blood pressure and to be a potent cerebrovascular risk factor. In this study, we showed that increased PAC is associated with CI.…”

Neurovascular function in Alzheimer's disease patients and experimental models

“…Topical superfusion of soluble Ab 1À40 on the mouse neocortex yielded results that were in line with the in vitro findings. It led to an attenuation of resting CBF and of the CBF increase evoked by whisker stimulation or by endotheliumdependent vasodilators, as measured by laser Doppler flowmetry (LDF) (Niwa et al, 2000a, b;Deane et al, 2003;Park et al, 2005;Takeda et al, 2009). These effects were abolished by free radical scavengers or by substitution of methionine with norleucin at residue 35 of Ab 1À40 , a modification that prevents free radical generation by the peptide (Niwa et al, 2000b).…”

“…In addition, APP mice feature impaired autoregulatory ability, a homeostatic mechanism that ensures constant blood flow during changes in mean arterial pressure. Animals thus lack protection against ischemia (Niwa et al, 2002b;Takeda et al, 2009). The CBF increase to hypercapnia and endothelium-independent vasodilators such as SNAP (S-nitroso-N-acetylpenicillamine) or SNP (sodium nitroprusside) is either maintained (Iadecola et al, 1999;Niwa et al, 2000a;Christie et al, 2001;Shin et al, 2007) or impaired (Park et al, 2005;Han et al, 2008) in young Tg2576 mice, suggesting variable degree of smooth muscle dysfunction.…”

“…Quantitative radioautographical determination of CGU showed intact resting and evoked glucose usage in Tg2123 mice (Niwa et al, 2000a), but a subsequent study showed reduced basal glucose utilization in Tg2576 mice that are derived from a different background strain and produce higher Ab levels (Niwa et al, 2002a). Recently, Takeda et al (2009) adjusted the magnitude of whisker stimulation so as to equalize somatosensory evoked potentials recorded at the site of CBF measurement. The authors were thus able to exclude that differences in neuronal activation accounted for the functional hyperemic deficit between 3-month-old WT and APP23 mice.…”

Ameliorative Effects of Telmisartan on the Inflammatory Response and Impaired Spatial Memory in a Rat Model of Alzheimer’s Disease Incorporating Additional Cerebrovascular Disease Factors

“…n=5-6 rats. ** telmisartan suppressed the expression of the proteolytic enzyme β-secretase, which produces Aβ from the beta-amyloid precursor protein (APP) 34) ; suppression of cerebral blood flow lowering in AD model animals inhibited the hypometabolism of Aβ 13,35) ; and acceleration of APP ubiquitination renders it easily degradable.…”