scholarly journals ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

2020 ◽  
Vol 139 (3) ◽  
pp. 485-502 ◽  
Author(s):  
Charles E. Evans ◽  
James S. Miners ◽  
Giulia Piva ◽  
Christine L. Willis ◽  
David M. Heard ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Animal Models ◽  
Cognitive Decline ◽  
Intraperitoneal Administration ◽  
Tg2576 Mouse ◽  
Model Of Alzheimer’S Disease ◽  
Increased Risk ◽  
Tg2576 Mice

Abstract Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer’s disease (AD). The classical renin–angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13–14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ42 and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9–10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12–13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.

scholarly journals Subjective cognitive decline: The first clinical manifestation of Alzheimer's disease?

2016 ◽  
Vol 10 (3) ◽  
pp. 170-177 ◽  
Author(s):  
Adalberto Studart Neto ◽  
Ricardo Nitrini
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Clinical Manifestation ◽  
Neurodegenerative Disorder ◽  
Subjective Cognitive Decline ◽  
Subjective Memory ◽  
Increased Risk

ABSTRACT Background: Mild cognitive impairment is considered as the first clinical manifestation of Alzheimer's disease (AD), when the individual exhibits below performance on standardized neuropsychological tests. However, some subjects before having a lower performance on cognitive assessments already have a subjective memory complaint. Objective: A review about subjective cognitive decline, the association with AD biomarkers and risk of conversion to dementia. Methods: We performed a comprehensive non-systematic review on PubMed. The keywords used in the search were terms related to subjective cognitive decline. Results: Subjective cognitive decline is characterized by self-experience of deterioration in cognitive performance not detected objectively through formal neuropsychological testing. However, various terms and definitions have been used in the literature and the lack of a widely accepted concept hampers comparison of studies. Epidemiological data have shown that individuals with subjective cognitive decline are at increased risk of progression to AD dementia. In addition, there is evidence that this group has a higher prevalence of positive biomarkers for amyloidosis and neurodegeneration. However, Alzheimer's disease is not the only cause of subjective cognitive decline and various other conditions can be associated with subjective memory complaints, such as psychiatric disorders or normal aging. The features suggestive of a neurodegenerative disorder are: onset of decline within the last five years, age at onset above 60 years, associated concerns about decline and confirmation by an informant. Conclusion: These findings support the idea that subjective cognitive complaints may be an early clinical marker that precedes mild cognitive impairment due to Alzheimer's disease.

scholarly journals Correction to: ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

2020 ◽  
Vol 140 (5) ◽  
pp. 791-791
Author(s):  
Charles E. Evans ◽  
James S. Miners ◽  
Giulia Piva ◽  
Christine L. Willis ◽  
David M. Heard ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Tg2576 Mouse ◽  
Amyloid Pathology ◽  
Model Of Alzheimer’S Disease

scholarly journals Cognitive and Disease-Modifying Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer's Disease

Endocrinology ◽  
2015 ◽  
Vol 156 (12) ◽  
pp. 4592-4603 ◽  
Author(s):  
Karen Sooy ◽  
June Noble ◽  
Andrew McBride ◽  
Margaret Binnie ◽  
Joyce L. W. Yau ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Hydroxysteroid Dehydrogenase ◽  
Insulin Degrading Enzyme ◽  
Short Term Treatment ◽  
Model Of Alzheimer’S Disease ◽  
The Brain ◽  
Tg2576 Mice

Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia.

Diabetes is associated with cognitive impairment no dementia in the aging, demographics, and memory study (ADAMS)

2012 ◽  
Vol 25 (1) ◽  
pp. 167-168 ◽  
Author(s):  
Christine E. Gould ◽  
Sherry A. Beaudreau ◽  
Huma Salman
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Vascular Dementia ◽  
Increased Risk ◽  
Cognitive Impairment No Dementia

Individuals with diabetes mellitus have a 1.39 times increased risk of Alzheimer's disease, a 2.38 times increased risk of vascular dementia, and a faster rate of cognitive decline compared to individuals without diabetes (Lu et al., 2009). In a study, over a 9-year follow-up diabetes was associated with accelerated progression from mild cognitive impairment (MCI) to dementia, but was not associated with progression from no impairment to MCI (Xu et al., 2010). Many previous studies on cognitive impairment and diabetes are limited by the use of cognitive screens to diagnose and assess cognitive impairment. A few studies diagnosing cognitive impairment with comprehensive neuropsychological batteries provide mixed results. For instance, Luchinger et al. (2007) found that diabetes was correlated with the presence of MCI, whereas diabetes was not associated with the presence of dementia versus no dementia in the Aging, Demographics, and Memory Study ADAMS; (Llewellyn et al., 2010).

scholarly journals A Comparative Analysis of Structural Brain MRI in the Diagnosis of Alzheimer’s Disease

2009 ◽  
Vol 21 (1-2) ◽  
pp. 13-19 ◽  
Author(s):  
Jason Appel ◽  
Elizabeth Potter ◽  
Qian Shen ◽  
Gustavo Pantol ◽  
Maria T. Greig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Medial Temporal Lobe ◽  
Rating Scales ◽  
Brain Mri ◽  
Alzheimer’S Dementia ◽  
Alzheimer's Dementia ◽  
Increased Risk

Dementia is a debilitating and life-altering disease which leads to both memory impairment and decline of normal executive functioning. While causes of dementia are numerous and varied, the leading cause among patients 60 years and older is Alzheimer’s disease. The gold standard for Alzheimer’s diagnosis remains histological identification of amyloid plaques and neurofibrillary tangles within the medial temporal lobe, more specifically the entorhinal cortex and hippocampus. Although no definitive cure for Alzheimer's disease currently exists, there are treatments targeted at preserving cognition and memory while delaying continued loss of function. Alzheimer's disease exists along a spectrum of cognitive decline and is often preceded by Mild Cognitive Impairment (MCI). Patients with MCI demonstrate memory loss and cognitive impairment while still continuing normal activities of daily living, and are considered to be at increased risk for developing Alzheimer's Dementia. Identifying patients with prodromal states of Alzheimer's dementia such as MCI may allow initiation of appropriate treatment planning and delay of cognitive decline. Therefore, the need for a non-invasive early biomarker for the detection of Alzheimer's disease has never been greater. Multiple neuroimaging methods utilizing visual rating scales, volumetric measurements, and automated methods have been developed to identify, quantify, and track anatomic sequelae of Alzheimer’s Disease.

Abstract TMP114: Cerebral Ischemia Combined With Amyloid Angiopathy Significantly Deteriorated Cognitive Impairment via Angiotensin AT1 Receptor in a Mouse Model of Alzheimer’s Disease

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Takashi Nakagawa ◽  
Yu Hasegawa ◽  
Shokei K Mitsuyama
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cerebral Ischemia ◽  
Cognitive Decline ◽  
Escape Latency ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mouse

Introduction: Ischemic stroke is suggested to be potentially associated with cognitive impairment in Alzheimer’s disease. Recent clinical data suggest that treatment with angiotensin receptor blocker (ARB) is associated with less incidence of Alzheimer’s disease than other classes of antihypertensive drugs. However, it is unknown whether cerebral ischemia can indeed trigger cognitive decline in Alzheimer’s disease and whether ARB can exert beneficial effect on ischemia-induced cognitive decline. Hypothesis: We hypothesized that cerebral ischemia deteriorates cognitive impairment in Alzheimer’s disease, through angiotensin II. Methods and results: We used 5XFAD mouse, a model of Alzheimer’s disease with vascular and cerebral amyloid-β(Aβ) deposition. Transient cerebral ischemia of mice was induced by bilateral common carotid artery occlusion (BCCAO) for 17 minutes. The post-treatment with olmesartan, an ARB, or vehicle was started at 24 hours after BCCAO, and was performed for 5 weeks. Mice were divided into 5 groups: (1) wild type, (2) wild type with BCCAO, (3) 5XFAD, (4) 5XFAD with BCCAO, (5) 5XFAD with BCCAO and olmesartan administration, to evaluate cognitive impairment. BCCAO in 5XFAD caused greater escape latency (p<0.01) on Water maze test (reference-/working-memory) and greater migration distance (p<0.05) on Open field test than that in wild type, indicating that cerebral ischemia combined with Aβ deposition enhanced cognitive decline. Post-treatment with olmesartan significantly reduced escape latency (p<0.01) on Water maze test, retention trial latency (p<0.05) on Passive avoidance test, and retention time of outer zone (p<0.01) on Open field test in 5XFAD subjected to BCCAO. BCCAO significantly deteriorated cognitive impairment, and this protection against BCCAO by olmesartan was associated with the protection of neuron in hippocampus and the suppression of blood-brain barrier disruption. Furthermore, olmesartan significantly attenuated brain oxidative stress, and NADPH oxidase subunits P67 in 5XFAD. Conclusion: We first demonstrated that cerebral ischemia combined with amyloid angiopathy markedly deteriorates cognitive impairment in 5XFAD mouse, through AT1 receptor.

scholarly journals Subtle Cognitive Decline predicts progression to Mild Cognitive Impairment Above and Beyond Alzheimer’s Disease Risk Factors

2019 ◽  
Vol 34 (6) ◽  
pp. 846-846
Author(s):  
J Osuna ◽  
K Thomas ◽  
E Edmonds ◽  
K Bangen ◽  
A Weigand ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Disease Risk ◽  
Preclinical Ad ◽  
Increased Risk

Abstract Objective Early identification of those at risk for mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is critical for early intervention. Recent work shows that subtle cognitive decline (SCD), operationally-defined using sensitive neuropsychological scores, predicts progression to MCI/AD and is associated with AD biomarkers. We aimed to determine whether SCD adds unique value in predicting progression to MCI/AD above and beyond other AD risk factors. Method 547 cognitively unimpaired participants from the Alzheimer’s Disease Neuroimaging Initiative (359 without SCD; 188 with SCD) underwent neuropsychological testing and lumbar puncture. Participants were classified as SCD if they performed >1 SD below the demographically-adjusted mean on 1) two neuropsychological total scores in different cognitive domains, or 2) two memory test process scores (e.g., intrusion errors), or 3) one total score and one process score. Cox regressions examined whether SCD status predicted progression to MCI and AD within 5 years after adjusting for age, education, sex, MMSE, depressive symptoms, ischemia risk, apolipoprotein E genotype, and AD biomarker “positivity” based on the cerebrospinal fluid phosphorylated tau-to-β-amyloid ratio. Results SCD status predicted progression to MCI (HR = 2.74, 95% CI = 2.07-3.63, p < .001) and AD (HR = 2.20, 95% CI = 1.04-4.65, p = .04) within 5 years, even after including known AD risk factors in the model. Conclusion SCD conveys a 2-3 fold increased risk of progression to MCI/AD and is a unique predictor above and beyond risk factors that are commonly used in preclinical AD research. These findings support our novel SCD criteria as a cost-effective and non-invasive method for identifying those at risk for future cognitive decline.

Subjective Spatial Navigation Complaints - A Frequent Symptom Reported by Patients with Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer's Disease

2018 ◽  
Vol 15 (3) ◽  
pp. 219-228 ◽  
Author(s):  
Jiri Cerman ◽  
Ross Andel ◽  
Jan Laczo ◽  
Martin Vyhnalek ◽  
Zuzana Nedelska ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Spatial Navigation ◽  
Subjective Cognitive Decline ◽  
Great Effort ◽  
Frequent Symptom ◽  
Normal Controls

Background: Great effort has been put into developing simple and feasible tools capable to detect Alzheimer's disease (AD) in its early clinical stage. Spatial navigation impairment occurs very early in AD and is detectable even in the stage of mild cognitive impairment (MCI). Objective: The aim was to describe the frequency of self-reported spatial navigation complaints in patients with subjective cognitive decline (SCD), amnestic and non-amnestic MCI (aMCI, naMCI) and AD dementia and to assess whether a simple questionnaire based on these complaints may be used to detect early AD. Method: In total 184 subjects: patients with aMCI (n=61), naMCI (n=27), SCD (n=63), dementia due to AD (n=20) and normal controls (n=13) were recruited. The subjects underwent neuropsychological examination and were administered a questionnaire addressing spatial navigation complaints. Responses to the 15 items questionnaire were scaled into four categories (no, minor, moderate and major complaints). Results: 55% of patients with aMCI, 64% with naMCI, 68% with SCD and 72% with AD complained about their spatial navigation. 38-61% of these complaints were moderate or major. Only 33% normal controls expressed complaints and none was ranked as moderate or major. The SCD, aMCI and AD dementia patients were more likely to express complaints than normal controls (p's<0.050) after adjusting for age, education, sex, depressive symptoms (OR for SCD=4.00, aMCI=3.90, AD dementia=7.02) or anxiety (OR for SCD=3.59, aMCI=3.64, AD dementia=6.41). Conclusion: Spatial navigation complaints are a frequent symptom not only in AD, but also in SCD and aMCI and can potentially be detected by a simple and inexpensive questionnaire.

Association Between the APOE ɛ2/ɛ4 Genotype and Alzheimer’s Disease and Mild Cognitive Impairment Among African Americans

2021 ◽  
pp. 1-6
Author(s):  
Dianxu Ren ◽  
Oscar L. Lopez ◽  
Jennifer H. Lingler ◽  
Yvette Conley
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
African Americans ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Increased Risk ◽  
Similar Risk

We examined the association between APOE ɛ2/ɛ4 with incident Alzheimer’s disease (AD) and mild cognitive impairment (MCI) among African Americans using the national dataset from the National Alzheimer’s Coordinating Center (NACC) from 2005 to September 2019. Compared to ɛ3/ɛ3 carriers, ɛ2/ɛ4 carriers exhibited a similar risk of incident AD (adjusted hazard ratio [aHR] = 0.85, 95% CI [0.39, 1.84]) among the AD cohort and similar risk of incident MCI (aHR = 0.88, 95% CI [0.51, 1.50]) among the MCI cohort. Our findings suggest that, unlike the increased risk of AD and MCI in non-Latino whites, APOE ɛ2/ɛ4 genotype is not associated with the incidence of AD and MCI among African Americans.

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