Interrelationship between Alzheimer’s disease and cardiac dysfunction: the brain–heart continuum?

2020 ◽  
Vol 52 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Mingjie Yang ◽  
Congye Li ◽  
Yingmei Zhang ◽  
Jun Ren
Keyword(s):  
Heart Failure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cardiovascular Diseases ◽  
Cardiac Dysfunction ◽  
Close Association ◽  
Amyloid Β ◽  
The Elderly ◽  
Cardiac Anomalies ◽  
Cardiac Pump Function

Abstract Dementia, a devastating neurological disorder commonly found in the elderly, is characterized by severe cognitive and memory impairment. Ample clinical and epidemiological evidence has depicted a close association between dementia and heart failure. While cerebral blood under perfusion and neurohormonal activation due to the dampened cardiac pump function contribute to the loss of nutrient supply and neuronal injury, Alzheimer’s disease (AD), the most common type of dementia, also provokes cardiovascular function impairment, in particular impairment of diastolic function. Aggregation of amyloid-β proteins and mutations of Presenilin (PSEN) genes are believed to participate in the pathological changes in the heart although it is still debatable with regards to the pathological cue of cardiac anomalies in AD process. In consequence, reduced cerebral blood flow triggered by cardiac dysfunction further deteriorates vascular dementia and AD pathology. Patients with atrial fibrillation, heart failure, and other cardiac anomalies are at a higher risk for cognitive decline and dementia. Conclusion: Due to the increased incidence of dementia and cardiovascular diseases, the coexistence of the two will cause more threat to public health, warranting much more attention. Here, we will update recent reports on dementia, AD, and cardiovascular diseases and discuss the causal relationship between dementia and heart dysfunction.

scholarly journals Astrocytes and Adenosine A2A Receptors: Active Players in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Cátia R. Lopes ◽  
Rodrigo A. Cunha ◽  
Paula Agostinho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Elderly ◽  
Synaptic Function ◽  
Morphological Alterations ◽  
Functional Changes ◽  
A2a Receptors ◽  
Novel Therapeutic Strategies

Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic “neurocentric” view of Alzheimer’s disease (AD), being astrocytes increasingly considered a key player in this neurodegenerative disease. AD, the most common form of dementia in the elderly, is characterized by a deterioration of memory and of other cognitive functions. Although, early cognitive deficits have been associated with synaptic loss and dysfunction caused by amyloid-β peptides (Aβ), accumulating evidences support a role of astrocytes in AD. Astrocyte atrophy and reactivity occurring at early and later stages of AD, respectively, involve morphological alterations that translate into functional changes. However, the main signals responsible for astrocytic alterations in AD and their impact on synaptic function remain to be defined. One possible candidate is adenosine, which can be formed upon extracellular catabolism of ATP released by astrocytes. Adenosine can act as a homeostatic modulator and also as a neuromodulator at the synaptic level, through the activation of adenosine receptors, mainly of A1R and A2AR subtypes. These receptors are also present in astrocytes, being particularly relevant in pathological conditions, to control the morphofunctional responses of astrocytes. Here, we will focus on the role of A2AR, since they are particularly associated with neurodegeneration and also with memory processes. Furthermore, A2AR levels are increased in the AD brain, namely in astrocytes where they can control key astrocytic functions. Thus, unveiling the role of A2AR in astrocytes function might shed light on novel therapeutic strategies for AD.

scholarly journals Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights

2020 ◽  
Vol 10 (3) ◽  
pp. 61 ◽  
Author(s):  
Chiara Villa ◽  
Marialuisa Lavitrano ◽  
Elena Salvatore ◽  
Romina Combi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Biological Fluids ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
The Elderly ◽  
Diagnostic Methods ◽  
Imaging Biomarkers ◽  
Attractive Alternative

Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, affecting millions of people worldwide and clinically characterized by a progressive and irreversible cognitive decline. The rapid increase in the incidence of AD highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods rely on measures of amyloid-β (Aβ), phosphorylated (p-tau) and total tau (t-tau) protein levels in the cerebrospinal fluid (CSF) aided by advanced neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). However, the invasiveness of these procedures and the high cost restrict their utilization. Hence, biomarkers from biological fluids obtained using non-invasive methods and novel neuroimaging approaches provide an attractive alternative for the early diagnosis of AD. Such biomarkers may also be helpful for better understanding of the molecular mechanisms underlying the disease, allowing differential diagnosis or at least prolonging the pre-symptomatic stage in patients suffering from AD. Herein, we discuss the advantages and limits of the conventional biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.

scholarly journals New pharmacological strategies for the treatment of alzheimer’s disease

2021 ◽  
Author(s):  
Letícia Freitas de Castro Silva ◽  
Elisa Pinheiro Weber ◽  
Gleice Silva Toledo ◽  
Josiane Fonseca Almeida
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Tau Protein ◽  
Amyloid Β ◽  
The Elderly ◽  
New Drugs ◽  
Pathophysiological Mechanisms ◽  
Apoe Protein ◽  
New Biomarkers

Introduction: Alzheimer’s disease (AD) is seen as the most important dementia, prevalent in the elderly over 60 years old. There is still no cure, and the pharmacological strategies are to delay the symptoms and development of the pathology. The pathophysiological mechanisms are: hyperphosphorylation of the tau protein and aggregation of amyloid-β. Update studies of the tested therapies target the main pathological mechanisms: accumulation of β amyloid (inhibitors and modulators of β-secretase and γ-secretase and active and passive anti-Aβ immunotherapies), tau protein (inhibition of abnormal hyperphosphorylation with GSK-3 inhibitors, passive and active immunotherapies and the use of intrathecal antisense oligonucleotides (ASOs) and correction of the ApoE protein (increase lipidation, correct structure, clearance of non-lipid ApoE and reduction of ApoE expression). Objectives and methodology: To develop a bibliographic review in order to address new drugs in the treatment of Alzheimer’s. Qualitative and descriptive study carried out by literary review with research on PubMed. Results: Several drugs have been tested in clinical trials, however, due to lack of effectiveness, none have been approved. Therefore, it’s important to understand the limitations of the tests developed as flaws in the methodology, insufficient understanding of the mechanisms involved and inclusion of patients in different stages of AD, so that future investigations can overcome these gaps. Conclusion: It’s important to investigate new pathophysiological mechanisms, as well as the factors that trigger AD. Diagnosis is essential, with further studies to identify new biomarkers of the disease that will also have an impact on the conduct of clinical trials.

Gut Microbiota and Alzheimer’s Disease: Pathophysiology and Therapeutic Perspectives

2021 ◽  
pp. 1-14
Author(s):  
Yanli Li ◽  
Rui Wang ◽  
Qian Li ◽  
Yan-Jiang Wang ◽  
Junhong Guo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Brain Function ◽  
Treatment Options ◽  
Amyloid Β ◽  
The Elderly ◽  
Protein Accumulation ◽  
Amyloid Β Protein ◽  
Dominant Bacteria

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive decline in cognitive function. Amyloid-β protein accumulation is believed to be the key pathological hallmark of AD. Increasing evidence has shown that the gut microbiota has a role in brain function and host behaviors. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine, and immune pathways. With increasing age, the gut microbiota diversity decreases, and the dominant bacteria change, which is closely related to systemic inflammation and health status. Dysbiosis of the gut microbiota is related to cognitive impairment and neurodegenerative diseases. The purpose of this review is to discuss the impacts of the gut microbiota on brain function and the development of AD. It is a feasible target for therapeutic invention. Modulating the composition of the gut microbiota through diet, physical activity or probiotic/prebiotic supplements can provide new prevention and treatment options for AD.

Flavonoids with Potential Anti-Amyloidogenic Effects as Therapeutic Drugs for Treating Alzheimer’s Disease

2021 ◽  
pp. 1-29
Author(s):  
Qixin Wang ◽  
Xiaofang Dong ◽  
Ran Zhang ◽  
Changqi Zhao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Aging ◽  
Positive Impact ◽  
Amyloid Β ◽  
The Elderly ◽  
Favorable Effect ◽  
Amyloid Β Protein ◽  
Physical And Mental Health ◽  
Dementia Patients

Alzheimer’s disease (AD) is a central neurodegenerative disease generally among the elderly; it accounts for approximately 50–75%of total cases of dementia patients and poses a serious threat to physical and mental health. Currently available treatments for AD mainly relieves its symptoms, and effective therapy is urgently needed. Deposition of amyloid-β protein in the brain is an early and invariant neuropathological feature of AD. Currently the main efforts in developing anti-AD drugs focus on anti-amyloidogenic therapeutics that prevent amyloid-β production or aggregation and decrease the occurrence of neurotoxic events. The results of an increasing number of studies suggest that natural extracts and phytochemicals have a positive impact on brain aging. Flavonoids belong to the broad group of polyphenols and recent data indicate a favorable effect of flavonoids on brain aging. In this review, we collect relevant discoveries from 1999 to 2021, discuss 75 flavonoids that effectively influence AD pathogenesis, and summarize their functional mechanisms in detail. The data we have reviewed show that, these flavonoids belong to various subclasses, including flavone, flavanone, biflavone, etc. Our results provide a reference for further study of the effects of flavonoids on AD and the progress of anti-AD therapy.

scholarly journals Alzheimer’s Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1215 ◽  
Author(s):  
Francisco Sáez-Orellana ◽  
Jean-Noël Octave ◽  
Nathalie Pierrot
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Amyloid Β ◽  
The Elderly ◽  
Special Focus ◽  
Peroxisome Proliferator ◽  
Amyloid Β Peptide ◽  
Peroxisome Proliferator Activated Receptor

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. Mutations in genes encoding proteins involved in amyloid-β peptide (Aβ) production are responsible for inherited AD cases. The amyloid cascade hypothesis was proposed to explain the pathogeny. Despite the fact that Aβ is considered as the main culprit of the pathology, most clinical trials focusing on Aβ failed and suggested that earlier interventions are needed to influence the course of AD. Therefore, identifying risk factors that predispose to AD is crucial. Among them, the epsilon 4 allele of the apolipoprotein E gene that encodes the major brain lipid carrier and metabolic disorders such as obesity and type 2 diabetes were identified as AD risk factors, suggesting that abnormal lipid metabolism could influence the progression of the disease. Among lipids, fatty acids (FAs) play a fundamental role in proper brain function, including memory. Peroxisome proliferator-activated receptor α (PPARα) is a master metabolic regulator that regulates the catabolism of FA. Several studies report an essential role of PPARα in neuronal function governing synaptic plasticity and cognition. In this review, we explore the implication of lipid metabolism in AD, with a special focus on PPARα and its potential role in AD therapy.

scholarly journals The role of proteotoxic stress in vascular dysfunction in the pathogenesis of Alzheimer’s disease

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Ana Catarina R.G. Fonseca ◽  
Rosa Resende ◽  
Sandra M. Cardoso ◽  
Cláudia F. Pereira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Vascular Endothelial Cells ◽  
Vascular Dysfunction ◽  
Progressive Failure ◽  
Amyloid Β ◽  
The Elderly ◽  
Endothelial Activation

AbstractAlzheimer’s disease (AD) is the principal cause of dementia in the elderly; however, its prevalence is increasing due to the fact that current pharmaceuticals used to manage the symptoms are not capable of preventing, halting, or reversing disease progression. In the last decade, evidence has accumulated to support the hypothesis that a primary cerebral vascular dysfunction initiates the cascade of events that leads to neuronal injury and the subsequent cognitive decline observed in AD. The mechanisms underlying these vascular defects and their relationship with neurodegeneration are still poorly understood however. It is pathologically known that cerebrovascular dysfunctions can induce the deposition of amyloid-β (Aβ), an amyloidogenic and toxic peptide that in turn causes cerebrovascular degeneration. Mammalian cells regulate proteostasis and the functioning of intracellular organelles through diverse mechanisms such as the Unfolded Protein Response, the Ubiquitin-Proteasome System and autophagy; however, when these mechanisms cannot compensate for perturbations in homeostasis, the cell undergoes programmed death via apoptosis. This review summarizes recent studies that together correlate the deregulation of protein quality control pathways with dysfunction of vascular endothelial cells of the brain in AD, thus supporting the hypothesis that it is the vicious, progressive failure of the proteostatic network and endothelial activation that underlies the cerebrovascular changes that symptomize AD.

Multiomics Investigation of Hypertension and White Matter Hyperintensity as a Source of Vascular Dementia or a Comorbidity to Alzheimer’s Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Gita A. Pathak ◽  
Robert C. Barbe ◽  
Nicole R. Phillips
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Amyloid Β ◽  
The Elderly ◽  
White Matter Hyperintensity ◽  
P Value ◽  
Csf Biomarkers ◽  
Age Related ◽  
Genome Wide

Background: Age-related comorbidity is common and significantly increases the burden for the healthcare of the elderly. Alzheimer’s disease (AD) and hypertension are the two most prevalent age-related conditions and are highly comorbid. While hypertension is a risk factor for vascular dementia (VD), hypertension with AD (ADHyp+) is often characterized as probable vascular dementia. In the absence of imaging and other diagnostic tests, differentiating the two pathological states is difficult. Objective: Our goals are to (1) identify differences in CSF-based vascular dementia profiles, if any, between individuals who have AD only (ADHyp-), and individuals with ADHyp+ using CSF levels of amyloid β, tau and p-tau, and (2) compare genome-wide DNA profiles of ADHyp- and AD-Hyp+ with an unaffected control population. Methods: Genotype and clinical data were used to compare healthy controls to AD+/Hyp- vs AD+/Hyp+. We compared the CSF biomarkers followed by evaluating genome wide profiles in three groups, and mapped SNPs to genes based on position and lowest p-value. The significant genes were examined for co-expression and known disease networks. Results: We found no differences between Aβ, tau and p-tau levels between ADHyp- and AD- Hyp+. We found TOMM40 to be associated with ADHyp- as expected but not with ADHyp+. Inter- estingly, SLC9A3R2 polymorphism was associated with ADHyp+, and significant gene expression changes were observed for neighboring genes. Conclusion: Through this exploratory study using a novel cohort stratification design, we highlight the genetic differences in clinically similar phenotypes, indicating the utility of genetic profiling in aiding differential diagnosis of ADHyp+ and VD.

scholarly journals Levetiracetam Alleviates Cognitive Decline in Alzheimer’s Disease Animal Model by Ameliorating the Dysfunction of the Neuronal Network

2021 ◽  
Author(s):  
Xiang-yu Zheng ◽  
Yu-Dan Lv ◽  
Feng-Yan Jin ◽  
Hai-Chen Zhang ◽  
Xiu-Juan Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Glycogen Synthase ◽  
Close Association ◽  
Amyloid Β ◽  
Network Activity ◽  
Amyloid Β Peptide ◽  
Low Concentrations ◽  
High Concentrations

Abstract Patients with Alzheimer’s disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)—a drug for treating seizures—on learning and memory and neuropathological features of AD. We bred APP23 mice with MAPT transgenic mice to generate APP23/MAPT mice. These were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months. The results revealed that low, but not high concentrations of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/β, thus rescuing neurons from synaptic dystrophy and apoptosis. Low concentrations of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid β-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of Aβ by reducing the expression of β site APP cleavage enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement abilities in mice, and did not improve cognitive decline in AD mice. Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. Low, but not high concentration of LEV may help ameliorate abnormalities in people who have or are at risk of AD.

scholarly journals Alzheimer’s Disease and microRNA-132: A Widespread Pathological Factor and Potential Therapeutic Target

2021 ◽  
Vol 15 ◽  
Author(s):  
Meng Zhang ◽  
Zhigang Bian
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Elderly ◽  
Clinical Results ◽  
Transcriptional Level ◽  
Amyloid Β Protein ◽  
Physiological Processes ◽  
Personality Changes ◽  
Gradual Onset

Alzheimer’s disease (AD) is a common neurodegenerative disease in the elderly and is the most common type of dementia. AD is mostly gradual onset, and involves slow, progressive mental decline, accompanied by personality changes; the incidence of AD gradually increases with age. The etiology of AD is unknown, although it is currently believed to be related to abnormal deposition of amyloid β-protein (Aβ) in the brain, hyperphosphorylation of microtubule-associated protein tau, and the release of various cytokines, complements, activators and chemokines by cells. MicroRNAs (miRNAs) are a class of highly conserved non-coding RNAs that regulate gene expression at the post-transcriptional level, and manipulate the functions of intracellular proteins and physiological processes. Emerging studies have shown that miRNA plays an important role in regulating AD-related genes. MiR-132 is known as “NeurimmiR” due to its involvement in numerous neurophysiological and pathological processes. Accumulating pre-clinical results suggest that miR-132 may be involved in the progression of Aβ and tau pathology. Moreover, clinical studies have indicated that decreased circulating miR-132 levels could be used a potential diagnostic biomarker in AD. Here, we review the pathogenic role of miR-132 activity in AD, and the potential of targeting miR-132 for developing future therapeutic strategies.

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