title: Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease.
abstract: Strong epidemiological and experimental evidence indicate that hypertension in the elderly predisposes to the development of Alzheimer's disease (AD), but the underlying mechanisms remain elusive. 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 (3 mo) and aged (24 mo) C57BL/6 mice by chronic (4 wk) infusion of angiotensin II and assessed changes in hippocampal mRNA expression of genes involved in amyloid precursor protein (APP)-dependent signaling, APP cleavage, Aβ processing and Aβ-degradation, synaptic function, dysregulation of microtubule-associated τ protein, and apolipoprotein-E signaling. Aged hypertensive mice exhibited spatial memory impairments in the Y-maze and impaired performance in the novel object recognition assay. Surprisingly, hypertension in aging did not increase the expression of APP, β- and γ-secretases, or genes involved in tauopathy. These genes are all involved in the early onset form of AD. Yet, hypertension in aging was associated with changes in hippocampal expression of APP binding proteins, e.g., [Mint3/amyloid β A4 precursor protein-binding family A member 3 (APBA3), Fe65/amyloid β A4 precursor protein-binding family B member 1 (APBB1)], amyloid β (A4) precursor-like protein 1 (APLP1), muscarinic M1 receptor, and serum amyloid P component, all of which may have a role in the pathogenesis of late-onset AD. The hippocampal gene expression signature observed in aged hypertensive mice in the present study provides important clues for subsequent studies to elucidate the mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of AD.
authors: Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors: Anna
authors: A
authors: Csiszar
authors: Zsuzsanna
authors: Z
authors: Tucsek
authors: Peter
authors: P
authors: Toth
authors: Danuta
authors: D
authors: Sosnowska
authors: Tripti
authors: T
authors: Gautam
authors: Akos
authors: A
authors: Koller
authors: Ferenc
authors: F
authors: Deak
authors: William E
authors: WE
authors: Sonntag
authors: Zoltan
authors: Z
authors: Ungvari
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism*; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D043643:Receptor, Muscarinic M1 / Q000235:genetics; D000683:Serum Amyloid P-Component / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C485530:Apba3 protein, mouse; C486243:Apbb1 protein, mouse; C078201:Aplp1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; D000683:Serum Amyloid P-Component; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; dementia; hypertension; senescence; tauopathy; vascular aging; vascular cognitive impairment; β-amyloid
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