Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex

Epidemiological data associate hypertension with a predisposition to Alzheimer’s disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid-β (Aβ) pathology. In contrast, anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in postmortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (n = 20) relative to normotensive cases (n = 62) and was also significantly higher in treated (n = 9) than untreated hypertensives (n = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesizing enzymes, β- and γ-secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (n = 21) than normotensive cases (n = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (n = 9) than untreated hypertensives (n = 12), possibly reflecting feedback upregulation of the renin-angiotensin system. Prospective studies in larger cohorts stratified according to anti-hypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments, and Aβ metabolism.

• Publication year

  2016

• Venue

  Journal of Alzheimer's Disease

• Publication date

  2016-01-19

• Fields of study

  Medicine

• Identifiers
  DOI 10.3233/JAD-150831PMID 26836178
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Alzheimer's disease neuroimaging

  2018cited by this paper
• Hypertension enhances Aβ-induced neurovascular dysfunction, promotes β-secretase activity, and leads to amyloidogenic processing of APP

  2016cited by this paper
• Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence.

  2015cited by this paper
• Hypertension Accelerates the Progression of Alzheimer-Like Pathology in a Mouse Model of the Disease

  2015cited by this paper
• Hypertension drives parenchymal β-amyloid accumulation in the brain parenchyma

  2014cited by this paper
• Arterial stiffness and β-amyloid progression in nondemented elderly adults.

  2014cited by this paper
• Aβ43 is the earliest-depositing Aβ species in APP transgenic mouse brain and is converted to Aβ41 by two active domains of ACE.

  2013cited by this paper
• A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

  2013cited by this paper
• Pericyte loss influences Alzheimer-like neurodegeneration in mice

  2013cited by this paper
• Prion Protein Is Decreased in Alzheimer's Brain and Inversely Correlates with BACE1 Activity, Amyloid-β Levels and Braak Stage

  2013cited by this paper
• Current status of renin–aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease

  2013cited by this paper
• Risk Factors for -Amyloid Deposition in Healthy Aging Vascular and Genetic Effects

  2013influential reference
• Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease.

  2013cited by this paper
• Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

  2013cited by this paper
• The Renin-Angiotensin System and Antihypertensive Drugs in Alzheimer's Disease: Current Standing of the Angiotensin Hypothesis?

  2012cited by this paper
• Impact of Angiotensin receptor blockers on Alzheimer disease neuropathology in a large brain autopsy series.

  2012cited by this paper
• National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

  2012cited by this paper
• Cardiovascular risk factors, cortisol, and amyloid‐β deposition in Alzheimer's Disease Neuroimaging Initiative

  2012cited by this paper
• Association between Chronic Blood Pressure Changes and Development of Alzheimer's Disease

  2012cited by this paper
• Central angiotensin II‐induced Alzheimer‐like tau phosphorylation in normal rat brains

  2012cited by this paper
• Hypertension Induces Brain &bgr;-Amyloid Accumulation, Cognitive Impairment, and Memory Deterioration Through Activation of Receptor for Advanced Glycation End Products in Brain Vasculature

  2012cited by this paper
• Selective Antihypertensive Dihydropyridines Lower Aβ Accumulation by Targeting both the Production and the Clearance of Aβ across the Blood-Brain Barrier

  2011cited by this paper
• Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy

  2011cited by this paper
• Association of Plasma Aß Peptides with Blood Pressure in the Elderly

  2011cited by this paper
• A&bgr;-Degrading Enzymes: Potential for Treatment of Alzheimer Disease

  2011cited by this paper
• Central Angiotensin II Stimulation Promotes β Amyloid Production in Sprague Dawley Rats

  2011cited by this paper
• National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach

  2011cited by this paper
• Accumulation of Insoluble Amyloid-β in Down's Syndrome is Associated with Increased BACE-1 and Neprilysin Activities

  2011cited by this paper
• Changes with Age in the Activities of β‐Secretase and the Aβ‐Degrading Enzymes Neprilysin, Insulin‐Degrading Enzyme and Angiotensin‐Converting Enzyme

  2010cited by this paper
• Oligomeric Aβ in Alzheimer's Disease: Relationship to Plaque and Tangle Pathology, APOE Genotype and Cerebral Amyloid Angiopathy

  2010cited by this paper
• Protective Effects of Intranasal Losartan in the APP/PS1 Transgenic Mouse Model of Alzheimer Disease

  2010cited by this paper
• Relationship of Hypertension, Blood Pressure, and Blood Pressure Control With White Matter Abnormalities in the Women’s Health Initiative Memory Study (WHIMS)—MRI Trial

  2010cited by this paper
• Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors

  2009cited by this paper
• Abeta42-to-Abeta40- and angiotensin-converting activities in different domains of angiotensin-converting enzyme.

  2009cited by this paper
• Identification of Antihypertensive Drugs Which Inhibit Amyloid-β Protein Oligomerization

  2009cited by this paper
• Neprilysin and Insulin-Degrading Enzyme Levels Are Increased in Alzheimer Disease in Relation to Disease Severity

  2009cited by this paper
• Characterisation of two antibodies to oligomeric Abeta and their use in ELISAs on human brain tissue homogenates.

  2009cited by this paper
• Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons

  2009cited by this paper
• Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses

  2009influential reference
• Structural neuroimaging in Alzheimer's disease: do white matter hyperintensities matter?

  2009cited by this paper
• Angiotensin-converting enzyme levels and activity in Alzheimer's disease: differences in brain and CSF ACE and association with ACE1 genotypes.

  2009cited by this paper
• Immunocapture-based fluorometric assay for the measurement of neprilysin-specific enzyme activity in brain tissue homogenates and cerebrospinal fluid.

  2008influential reference
• Amyloid-degrading enzymes as therapeutic targets in Alzheimer's disease.

  2008cited by this paper
• Angiotensin‐converting enzyme (ACE) levels and activity in Alzheimer's disease, and relationship of perivascular ACE‐1 to cerebral amyloid angiopathy

  2008cited by this paper
• Immunocapture-based fluorometric assay for the measurement of insulin-degrading enzyme activity in brain tissue homogenates.

  2008cited by this paper
• Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.

  2007cited by this paper
• Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment.

  2007cited by this paper
• Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition enhances brain Abeta deposition.

  2007cited by this paper
• Angiotensin-Converting Enzyme Converts Amyloid β-Protein 1–42 (Aβ1–42) to Aβ1–40, and Its Inhibition Enhances Brain Aβ Deposition

  2007cited by this paper
• G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences

  2007cited by this paper
• Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry

  2006cited by this paper
• Decreased Expression and Activity of Neprilysin in Alzheimer Disease Are Associated With Cerebral Amyloid Angiopathy

  2006cited by this paper
• Effect of Hypoxia/Ischemia and Hypoxic Preconditioning/Reperfusion on Expression of Some Amyloid‐Degrading Enzymes

  2004cited by this paper
• APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein.

  2003cited by this paper
• APOEɛ4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of Aβ protein

  2003cited by this paper
• Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS☆

  2000cited by this paper
• Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study.

  2000cited by this paper
• Hypoperfusion induces overexpression of beta-amyloid precursor protein mRNA in a focal ischemic rodent model.

  2000cited by this paper
• Post‐ischemic changes in the expression of Alzheimer's APP isoforms in rat cerebral cortex

  1998cited by this paper
• Coronary Artery Disease, Hypertension, ApoE, and Cholesterol: A Link to Alzheimer's Disease?

  1997cited by this paper
• The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study.

  1995cited by this paper
• Increased incidence of neurofibrillary tangles (NFT) in non-demented individuals with hypertension.

  1995cited by this paper
• Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

  1993cited by this paper
• Ultrastructural changes in cerebral pericytes and astrocytes of stroke-prone spontaneously hypertensive rats.

  1990cited by this paper

• Angiotensin II–Stimulating Antihypertensive Medications and Dementia-Related Neuropathology

  2026cites this paper
• Heat Therapy: Targeting Health, Disease, and Disability

  2026cites this paper
• Biophysical analysis of angiotensin II and amyloid‐β cross‐interaction in aggregation and membrane disruption

  2025cites this paper
• Peripheral Leukocyte Syndecan-3 Is Elevated in Alzheimer’s Disease: Evidence from a Human Study

  2025cites this paper
• Elevated late-life blood pressure may maintain brain oxygenation and slow amyloid-β accumulation at the expense of cerebral vascular damage

  2023cites this paper
• Past antihypertensive medication use is associated with lower levels of small vessel disease and lower Aβ plaque stage in the brains of older individuals

  2023cites this paper
• Is later-life depression a risk factor for Alzheimer’s disease or a prodromal symptom: a study using post-mortem human brain tissue?

  2023cites this paper
• Incidence of Alzheimer’s Disease in Men with Late-Life Hypertension Is Ameliorated by FOXO3 Longevity Genotype

  2023cites this paper
• The Association Between 24-Hour Blood Pressure Profiles and Dementia

  2023cites this paper
• Oestrogenic Regulation of Mitochondrial Dynamics

  2022cites this paper
• Effects of Hypertension on Alzheimer’s Disease and Related Disorders

  2022cites this paper
• Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT_4R) in the postmortem brains of individuals without cognitive impairment

  2022cites this paper
• Risk factors for cognitive decline in type 2 diabetes mellitus patients in Brazil: a prospective observational study

  2022cites this paper
• Correlation of Cerebral Atrophy and White Matter Hyperintensity Burden in MRI with Clinical Cognitive Decline

  2022cites this paper
• Mental disorders and poor COVID-19 prognosis: reevaluating the relationship through Ca2+/cAMP signalling.

  2022cites this paper
• Effects of dietary restriction on cognitive function: a systematic review and meta-analysis

  2022cites this paper
• Short-Term Pharmacological Induction of Arterial Stiffness and Hypertension with Angiotensin II Does Not Affect Learning and Memory and Cerebral Amyloid Load in Two Murine Models of Alzheimer’s Disease

  2022cites this paper
• The Interaction Between Vascular Risk Factors, Cerebral Small Vessel Disease, and Amyloid Burden in Older Adults

  2022cites this paper
• A timeline of Ca2+/cAMP signalling: From basic research to potential therapeutics for dementia.

  2022cites this paper
• Kinin B1R Activation Induces Endoplasmic Reticulum Stress in Primary Hypothalamic Neurons

  2022cites this paper
• Promoting Successful Cognitive Aging: A Ten-Year Update

  2021cites this paper
• Prevalence of mild cognitive impairment in patients with hypertension: a systematic review and meta-analysis

  2021cites this paper
• Amyloid Goiter in Renal Transplantation and Chronic Systemic Diseases; Literature Review with Six Case Reports

  2020cites this paper
• Neprilysin: A Potential Therapeutic Target of Arterial Hypertension?

  2020cites this paper
• Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages

  2020cites this paper
• Antihypertensive medications ameliorate Alzheimer's disease pathology by slowing its propagation

  2020cites this paper
• Heat therapy: possible benefits for cognitive function and the aging brain.

  2020cites this paper
• Hypertension and Alzheimer’s disease: indirect effects through circle of Willis atherosclerosis

  2020cites this paper
• Research Progress of Alzheimer’s Disease Therapeutic Drugs: Based on Renin-Angiotensin System Axis

  2020cites this paper
• The role of blood pressure and hypertension in dementia

  2020cites this paper
• Associations between brain amyloid accumulation and the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers.

  2020cites this paper
• Blood Pressure Control and Protection of the Aging Brain

  2019cites this paper
• Antihypertensive agents in Alzheimer’s disease: beyond vascular protection

  2019cites this paper
• Hypertension, Diabetes and Neurodegenerative Diseases: Is there a Clinical Link through the Ca2+/cAMP Signalling Interaction?

  2019cites this paper
• Pregnancy History, Hypertension, and Cognitive Impairment in Postmenopausal Women

  2019cites this paper
• Renin-angiotensin system and Alzheimer's disease pathophysiology: From the potential interactions to therapeutic perspectives.

  2019cites this paper
• The influence of life course vascular risk on brain pathologies and cognition in later life - a neuroimaging study of the British 1946 birth cohort

  2019cites this paper
• Axon Initial Segment Integrity in Aging and Traumatic Brain Injury

  2019cites this paper
• Patient Perceptions of Antihypertensive Use as a Dementia Prevention Strategy: A Mixed-Method Analysis of a Web-Based Survey

  2019cites this paper
• Sacubitril/valsartan: a cardiovascular drug with pluripotential actions.

  2018cites this paper
• The Role of Long Noncoding RNAs in Diabetic Alzheimer’s Disease

  2018cites this paper
• The Down-Expression of ACE and IDE Exacerbates Exogenous Amyloid-β Neurotoxicity in CB2R–/– Mice

  2018cites this paper
• The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease

  2018cites this paper
• Benefits and pitfalls of sacubitril/valsartan treatment in patients with hypertension

  2018cites this paper
• N-domain of angiotensin-converting enzyme hydrolyzes human and rat amyloid-β(1-16) peptides as arginine specific endopeptidase potentially enhancing risk of Alzheimer’s disease

  2018cites this paper
• Obstructive Sleep Apnea is Associated With Early but Possibly Modifiable Alzheimer’s Disease Biomarkers Changes

  2017cites this paper
• Cerebral Aβ40 and systemic hypertension

  2017cites this paper
• Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/valsartan.

  2017cites this paper
• Insulin signaling: An opportunistic target to minify the risk of Alzheimer's disease.

  2017cites this paper
• Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer’s (HEART) Trial

  2017cites this paper
• Effect of folic acid combined with routine drugs on Hcy metabolism , inflammatory response and plaque properties in patients with H-type hypertension complicated by carotid atherosclerosis

  2017cites this paper
• Defining the Relationship Between Hypertension, Cognitive Decline, and Dementia: a Review

  2017cites this paper
• Vascular cognitive impairment neuropathology guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment.

  2016cites this paper
• Fuzhisan ameliorates Aβ production and tau phosphorylation in hippocampal of 11month old APP/PS1 transgenic mice: A Western blot study.

  2016cites this paper