Hypertension enhances Aβ-induced neurovascular dysfunction, promotes β-secretase activity, and leads to amyloidogenic processing of APP.
Hypertension (HTN) doubles the risk of Alzheimer’s disease (AD), but the mechanisms remain unclear. Amyloid-β (Aβ), a key pathogenic factor in AD, induces cerebrovascular dysfunction. We hypothesized that HTN acts in concert with Aβ to amplify its deleterious cerebrovascular effects and to increase Aβ production. Infusion of angiotensin II (ANGII; intravenously) elevated blood pressure and attenuated the cerebral blood flow (CBF) response to whisker stimulation or the endothelium-dependent vasodilator acetylcholine (ACh) (P < 0.05). Neocortical application of Aβ in mice receiving ANGII worsened the responses to ACh (P < 0.05). The cerebrovascular dysfunction observed in Tg2576 mice, in which Aβ is elevated both in blood and in brain due to expression of mutated amyloid precursor protein (APP), was not aggravated by neocortical application of ANGII or by a 2-week administration of ‘slow pressor’ of ANGII (600 ng/kg per minute; subcutaneously). In contrast, ANGII aggravated the dysfunction in TgSwDI mice, in which Aβ is increased only in brain. Slow-pressor ANGII induced microvascular amyloid deposition in Tg2576 mice and enhanced β-secretase APP cleavage. In Chinese hamster ovary (CHO) cells producing Aβ, ANGII increased β-secretase activity, Aβ1-42, and the Aβ42/40 ratio. We conclude that HTN enhances amyloidogenic APP processing, effects that may contribute to the pathogenic interaction between HTN and AD.
Giuseppe
G
Faraco
Laibaik
L
Park
Ping
P
Zhou
Wenjie
W
Luo
Steven M
SM
Paul
Josef
J
Anrather
Costantino
C
Iadecola
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000097:blood / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003412:Cricetulus; D004195:Disease Models, Animal; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000804:Angiotensin II; D053829:Amyloid Precursor Protein Secretases