TY - JOUR
T1 - Synergistic effects of hypertension and aging on cognitive function and Hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease
AU - Csiszar, Anna
AU - Tucsek, Zsuzsanna
AU - Toth, Peter
AU - Sosnowska, Danuta
AU - Gautam, Tripti
AU - Koller, Akos
AU - Deak, Ferenc
AU - Sonntag, William E.
AU - Ungvari, Zoltan
PY - 2013/10/15
Y1 - 2013/10/15
N2 - 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 βA4 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.
AB - 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 βA4 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.
KW - Alzheimer's disease
KW - Dementia
KW - Hypertension
KW - Senescence
KW - Tauopathy
KW - Vascular aging
KW - Vascular cognitive impairment
KW - β-amyloid
UR - http://www.scopus.com/inward/record.url?scp=84885593973&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885593973&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00288.2013
DO - 10.1152/ajpheart.00288.2013
M3 - Article
C2 - 23955715
AN - SCOPUS:84885593973
SN - 0363-6135
VL - 305
SP - H1120-H1130
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 8
ER -