scholarly journals Large Artery Stiffness and Brain Health: Insights from Animal Models

2020 ◽  
Author(s):  
Nicholas R Winder ◽  
Emily H Reeve ◽  
Ashley E Walker
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Brain Aging ◽  
Large Artery ◽  
Neurocognitive Dysfunction ◽  
Disease Etiology ◽  
Age Related ◽  
Artery Stiffness ◽  
Underlying Mechanisms

There are no effective treatments available to halt or reverse the progression of age-related cognitive decline and Alzheimer's disease. Thus, there is an urgent need to understand the underlying mechanisms of disease etiology and progression in order to identify novel therapeutic targets. Age-related changes to vasculature, particularly increases in stiffness of the large elastic arteries, are now recognized as important contributors to brain aging. There is a growing body of evidence for an association between greater large artery stiffness and cognitive impairment among both healthy older adults and patients with Alzheimer's disease. However, studies in humans are limited to only correlative evidence while animal models allow researchers to explore the causative mechanisms linking arterial stiffness to neurocognitive dysfunction and disease. Recently, several rodent models of direct modulation of large artery stiffness and the consequent effects on the brain have been reported. Common outcomes among these models have emerged, including evidence that greater large artery stiffness causes cerebrovascular dysfunction associated with increased oxidative stress and inflammatory signaling. The purpose of this mini review is to highlight recent findings associating large artery stiffness with deleterious brain outcomes, with a specific focus on causative evidence obtained from animal models. We will also discuss the gaps in knowledge that remain in our understanding of how large artery stiffness affects brain function and disease outcomes.

scholarly journals Overview of Alzheimer’s Disease and Some Therapeutic Approaches Targeting Aβby Using Several Synthetic and Herbal Compounds

2016 ◽  
Vol 2016 ◽  
pp. 1-22 ◽  
Author(s):  
Sandeep Kumar Singh ◽  
Saurabh Srivastav ◽  
Amarish Kumar Yadav ◽  
Saripella Srikrishna ◽  
George Perry
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Neurodegenerative Disease ◽  
Therapeutic Approaches ◽  
Age Related

Alzheimer’s disease (AD) is a complex age-related neurodegenerative disease. In this review, we carefully detail amyloid-βmetabolism and its role in AD. We also consider the various genetic animal models used to evaluate therapeutics. Finally, we consider the role of synthetic and plant-based compounds in therapeutics.

scholarly journals Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s Disease

2020 ◽  
Author(s):  
James M. Roe ◽  
Didac Vidal-Piñeiro ◽  
Øystein Sørensen ◽  
Andreas M. Brandmaier ◽  
Sandra Düzel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hemispheric Asymmetry ◽  
Temporal Dynamics ◽  
Brain Aging ◽  
Hemispheric Specialization ◽  
Adult Life ◽  
Adult Lifespan ◽  
Age Related ◽  
Cortical Asymmetry

AbstractNormal aging and Alzheimer’s Disease (AD) are accompanied by large-scale alterations in brain organization that undermine brain function. Although hemispheric asymmetry is a global organizing feature of cortex thought to promote brain efficiency, current descriptions of cortical thinning in aging and AD have largely overlooked cortical asymmetry. Consequently, the foundational question of whether and where the cerebral hemispheres change at different rates in aging and AD remains open. First, applying vertex-wise data-driven clustering in a longitudinal discovery sample (aged 20-89; 2577 observations; 1851 longitudinal) we identified cortical regions exhibiting similar age-trajectories of asymmetry across the adult lifespan. Next, we sought replication in 4 independent longitudinal aging cohorts. We show that higher-order regions of cortex that exhibit pronounced asymmetry at age ~20 also show asymmetry change in aging. Results revealed that both leftward and rightward asymmetry is progressively lost on a similar time-scale across adult life. Hence, faster thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This simple organizational principle showed high consistency across multiple aging cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Finally, we show that regions exhibiting gradual asymmetry-loss over healthy adult life exhibit faster asymmetry-change in AD.Overall, our results suggest a system-wide breakdown in the adaptive asymmetric organization of cortex across adult life which is further accelerated in AD, and may implicate thickness asymmetry as a viable marker for declining hemispheric specialization in aging and AD.SignificanceThe brain becomes progressively disorganized with age, and brain alterations accelerated in Alzheimer’s disease may occur gradually over the lifespan. Although hemispheric asymmetry aids efficient network organization, efforts to identify structural markers of age-related decline have largely overlooked cortical asymmetry. Here we show the hemisphere that is thicker when younger, thins faster. This leads to progressive system-wide loss of regional thickness asymmetry across life. In multiple aging cohorts, asymmetry-loss showed high reproducibility topologically across cortex and similar timing-of-change in aging. Asymmetry-change was further accelerated in AD. Our findings uncover a new principle of brain aging – thicker homotopic cortex thins faster – and suggest we may have unveiled a structural marker for a widely-hypothesized decline in hemispheric specialization in aging and AD.

scholarly journals Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1138
Author(s):  
Melissa K. Edler ◽  
Isha Mhatre-Winters ◽  
Jason R. Richardson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Single Species ◽  
Functional Behavior ◽  
Age Related ◽  
Rapid Changes ◽  
The Central Nervous System ◽  
Oxidative Species ◽  
Selection Of

Microglia are the primary immune cells of the central nervous system that help nourish and support neurons, clear debris, and respond to foreign stimuli. Greatly impacted by their environment, microglia go through rapid changes in cell shape, gene expression, and functional behavior during states of infection, trauma, and neurodegeneration. Aging also has a profound effect on microglia, leading to chronic inflammation and an increase in the brain’s susceptibility to neurodegenerative processes that occur in Alzheimer’s disease. Despite the scientific community’s growing knowledge in the field of neuroinflammation, the overall success rate of drug treatment for age-related and neurodegenerative diseases remains incredibly low. Potential reasons for the lack of translation from animal models to the clinic include the use of a single species model, an assumption of similarity in humans, and ignoring contradictory data or information from other species. To aid in the selection of validated and predictive animal models and to bridge the translational gap, this review evaluates similarities and differences among species in microglial activation and density, morphology and phenotype, cytokine expression, phagocytosis, and production of oxidative species in aging and Alzheimer’s disease.

scholarly journals Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Xin Zhang ◽  
Nadine Alshakhshir ◽  
Liqin Zhao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Brain Aging ◽  
Redox Homeostasis ◽  
Critical Role ◽  
Glycolytic Flux ◽  
Glycolytic Metabolism ◽  
Age Related ◽  
Brain Resilience

Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

scholarly journals Current State of the Art in Preclinical Research in Alzheimer’s Disease - A Focus on Mode of Action in Pharmacological and Non-pharmacological Approaches

2012 ◽  
Vol 7 (4) ◽  
pp. 216
Author(s):  
Kiren Ubhi ◽  
Eliezer Masliah ◽  
◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Cholinergic Neurons ◽  
Therapeutic Approaches ◽  
Preclinical Research ◽  
Current State ◽  
Age Related ◽  
Cognitive Disturbances ◽  
Underlying Mechanisms

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterised by progressive memory deficits and other cognitive disturbances. Neuropathologically, AD is characterised by synaptic deficits, progressive loss of neocortical, limbic and basal forebrain cholinergic neurons and the abnormal extracellular accumulation of amyloid-beta (Aß) and the intracellular aggregation of the cvtoskeletal protein tau. Currently available AD therapies either only temporarily delay disease progression or address the symptoms but are unable to alter the underlying mechanisms of disease. Therefore, ongoing AD research is focused at better understanding pathogenesis and at developing disease-modifying experimental therapeutic approaches. This review will summarise the main areas of preclinical research for AD therapeutics that includes those aimed at modulating the processing of amyloid precursor protein (APP) and the production of Aß; ameliorating the pathological accumulation of Aß or tau; augmenting neuroprotective activities in the AD brain; and augmenting neurorestoration in the AD brain. The review will also discuss a novel multimodal therapeutic approach to AD using Cerebrolysin, a peptidergic mixture with neurotrophic-like effects.

scholarly journals Transitions in metabolic and immune systems from pre-menopause to post-menopause: implications for age-associated neurodegenerative diseases

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 68 ◽  
Author(s):  
Yiwei Wang ◽  
Aarti Mishra ◽  
Roberta Diaz Brinton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Aging Process ◽  
Brain Aging ◽  
Hormone Replacement ◽  
Low Grade ◽  
Chronological Aging ◽  
Age Related ◽  
Female Brain

The brain undergoes two aging programs: chronological and endocrinological. This is particularly evident in the female brain, which undergoes programs of aging associated with reproductive competency. Comprehensive understanding of the dynamic metabolic and neuroinflammatory aging process in the female brain can illuminate windows of opportunities to promote healthy brain aging. Bioenergetic crisis and chronic low-grade inflammation are hallmarks of brain aging and menopause and have been implicated as a unifying factor causally connecting genetic risk factors for Alzheimer’s disease and other neurodegenerative diseases. In this review, we discuss metabolic phenotypes of pre-menopausal, peri-menopausal, and post-menopausal aging and their consequent impact on the neuroinflammatory profile during each transition state. A critical aspect of the aging process is the dynamic metabolic neuro-inflammatory profiles that emerge during chronological and endocrinological aging. These dynamic systems of biology are relevant to multiple age-associated neurodegenerative diseases and provide a therapeutic framework for prevention and delay of neurodegenerative diseases of aging. While these findings are based on investigations of the female brain, they have a broader fundamental systems of biology strategy for investigating the aging male brain. Molecular characterization of alterations in fuel utilization and neuroinflammatory mechanisms during these neuro-endocrine transition states can inform therapeutic strategies to mitigate the risk of Alzheimer’s disease in women. We further discuss a precision hormone replacement therapy approach to target symptom profiles during endocrine and chronological aging to reduce risk for age-related neurodegenerative diseases.

scholarly journals Hippocampal Perfusion in a Mouse Model of Greater Large Artery Stiffness and Alzheimer’s Disease‐Related Transgenes

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Nicholas R. Winder ◽  
Grant D. Henson ◽  
Martin M. Pike ◽  
Ashley E. Walker
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Large Artery ◽  
Artery Stiffness
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