Mechanosensing and the Hippo Pathway in Microglia: A Potential Link to Alzheimer’s Disease Pathogenesis?

The activation of microglia, the inflammatory cells of the central nervous system (CNS), has been linked to the pathogenesis of Alzheimer’s disease and other neurodegenerative diseases. How microglia sense the changing brain environment, in order to respond appropriately, is still being elucidated. Microglia are able to sense and respond to the mechanical properties of their microenvironment, and the physical and molecular pathways underlying this mechanosensing/mechanotransduction in microglia have recently been investigated. The Hippo pathway functions through mechanosensing and subsequent protein kinase cascades, and is critical for neuronal development and many other cellular processes. In this review, we examine evidence for the potential involvement of Hippo pathway components specifically in microglia in the pathogenesis of Alzheimer’s disease. We suggest that the Hippo pathway is worth investigating as a mechanosensing pathway in microglia, and could be one potential therapeutic target pathway for preventing microglial-induced neurodegeneration in AD.

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The relationship of diabetes mellitus with Alzheimer’s disease: a literature review

10.5327/1516-3180.280 ◽

2021 ◽

Author(s):

Fábio Dias Nogueira ◽

Ana Klara Rodrigues Alves ◽

Barbara Beatriz Lira da Silva ◽

Ana Kamila Rodrigues Alves ◽

Marlilia Moura Coelho Sousa ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Potential Link ◽

The Central Nervous System ◽

Gsk 3Β ◽

Type 3 ◽

The Brain

Introduction: Alzheimer’s disease (AD) is closely related to diabetes mellitus (DM), and AD is also considered to be type 3 diabetes (T3D). Glycogen synthase kinase-3β (GSK-3β) may be the potential link between DM and AD. GSK-3β is one of the main factors that lead to insulin deficiency and insulin resistance, and insulin resistance is a characteristic of the development of DM. In AD, GSK-3β plays an important role in hyperphosphorylation of the tau protein (tau) associated with microtubules, which is one of the pathological features in AD. Objective: To analyze DM as a factor for the development of AD. METHODOLOGY: This is an integrative review of the literature, which is a construction of a comprehensive analysis of the literature with pre-defined steps, carried out through PubMed, 1.501 articles were found, of which 10 were selected, through the simultaneous crossing between the descriptors “Diabetes mellitus”, “Alzheimer “. Articles written in Portuguese and English published between 2016 and 2021 were inserted. Results: DM associated with insulin resistance affects psychomotor efficiency, attention, learning memory, mental flexibility, speed and executive function of the brain, thus being an independent risk factor for cognitive impairment and damage to the central nervous system, hyperglycemia, which can cause increased oxidative stress leading to progressive functional and structural abnormalities in the brain. Conclusion:The risk of dementia in patients with DM is higher than in nondiabetic patients and it is also well known that DM2 / insulin resistance is involved in AD.

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Neuroinflammation and Copper in Alzheimer’s Disease

International Journal of Alzheimer s Disease ◽

10.1155/2013/145345 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 14

Author(s):

Xin Yi Choo ◽

Lobna Alukaidey ◽

Anthony R. White ◽

Alexandra Grubman

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inflammatory Responses ◽

Critical Role ◽

Inflammatory Cells ◽

Damage Initiation ◽

Activated Microglia ◽

Cu Deficiency ◽

Rapid Responses ◽

The Central Nervous System

Inflammation is the innate immune response to infection or tissue damage. Initiation of proinflammatory cascades in the central nervous system (CNS) occurs through recognition of danger associated molecular patterns by cognate immune receptors expressed on inflammatory cells and leads to rapid responses to remove the danger stimulus. The presence of activated microglia and astrocytes in the vicinity of amyloid plaques in the brains of Alzheimer’s disease (AD) patients and mouse models implicates inflammation as a contributor to AD pathogenesis. Activated microglia play a critical role in amyloid clearance, but chronic deregulation of CNS inflammatory pathways results in secretion of neurotoxic mediators that ultimately contribute to neurodegeneration in AD. Copper (Cu) homeostasis is profoundly affected in AD, and accumulated extracellular Cu drives Aβaggregation, while intracellular Cu deficiency limits bioavailable Cu required for CNS functions. This review presents an overview of inflammatory events that occur in AD in response to Aβand highlights recent advances on the role of Cu in modulation of beneficial and detrimental inflammatory responses in AD.

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Sirtuins as Potential Therapeutic Targets for Mitigating Neuroinflammation Associated With Alzheimer’s Disease

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.746631 ◽

2021 ◽

Vol 15 ◽

Author(s):

Kurukulasooriya Kavindya Madushani Fernando ◽

Yasanandana Supunsiri Wijayasinghe

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation ◽

Neurodegenerative Disorder ◽

Therapeutic Interventions ◽

Cellular Processes ◽

Dependent Protein ◽

The Central Nervous System ◽

Β Amyloid ◽

With Memory

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which is associated with memory deficit and global cognitive decline. Age is the greatest risk factor for AD and, in recent years, it is becoming increasingly appreciated that aging-related neuroinflammation plays a key role in the pathogenesis of AD. The presence of β-amyloid plaques and neurofibrillary tangles are the primary pathological hallmarks of AD; defects which can then activate a cascade of molecular inflammatory pathways in glial cells. Microglia, the resident macrophages in the central nervous system (CNS), are the major triggers of inflammation; a response which is typically intended to prevent further damage to the CNS. However, persistent microglial activation (i.e., neuroinflammation) is toxic to both neurons and glia, which then leads to neurodegeneration. Growing evidence supports a central role for sirtuins in the regulation of neuroinflammation. Sirtuins are NAD+-dependent protein deacetylases that modulate a number of cellular processes associated with inflammation. This review examines the latest findings regarding AD-associated neuroinflammation, mainly focusing on the connections among the microglial molecular pathways of inflammation. Furthermore, we highlight the biology of sirtuins, and their role in neuroinflammation. Suppression of microglial activity through modulation of the sirtuin activity has now become a key area of research, where progress in therapeutic interventions may slow the progression of Alzheimer’s disease.

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Paired helical filaments (PHF) in rats: An experimental animal model for Alzheimer's disease

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128493 ◽

1987 ◽

Vol 45 ◽

pp. 842-843

Author(s):

V.J.A. Montpetit ◽

S. Dancea ◽

S.W. French ◽

D.F. Clapin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Model ◽

Paired Helical Filaments ◽

Ethanol Intoxication ◽

Drg Neurons ◽

Critical Difference ◽

Suitable Animal Model ◽

The Central Nervous System ◽

Chronic Ethanol Intoxication

A continuing problem in Alzheimer research is the lack of a suitable animal model for the disease. The absence of neurofibrillary tangles of paired helical filaments is the most critical difference in the processes by which the central nervous system ages in most species other than man. However, restricting consideration to single phenomena, one may identify animal models for specific aspects of Alzheimer's disease. Abnormal fibers resembling PHF have been observed in dorsal root ganglia (DRG) neurons of rats in a study of chronic ethanol intoxication and spontaneously in aged rats. We present in this report evidence that PHF-like filaments occur in ethanol-treated rats of young age. In control animals lesions similar in some respects to our observations of cytoskeletal pathology in pyridoxine induced neurotoxicity were observed.Male Wistar BR rats (Charles River Labs) weighing 350 to 400 g, were implanted with a single gastrostomy cannula and infused with a liquid diet containing 30% of total calories as fat plus ethanol or isocaloric dextrose.

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Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems

Current Drug Targets ◽

10.2174/1389450120666191118123151 ◽

2020 ◽

Vol 21 (7) ◽

pp. 628-646

Author(s):

Gülcem Altinoglu ◽

Terin Adali

Keyword(s):

Alzheimer’S Disease ◽

Drug Delivery ◽

Alzheimer's Disease ◽

Neurological Diseases ◽

Sustained Drug Release ◽

Physiochemical Properties ◽

Conventional Drug ◽

Health Care Burden ◽

The Central Nervous System ◽

Effective Drugs

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and is part of a massive and growing health care burden that is destroying the cognitive function of more than 50 million individuals worldwide. Today, therapeutic options are limited to approaches with mild symptomatic benefits. The failure in developing effective drugs is attributed to, but not limited to the highly heterogeneous nature of AD with multiple underlying hypotheses and multifactorial pathology. In addition, targeted drug delivery to the central nervous system (CNS), for the diagnosis and therapy of neurological diseases like AD, is restricted by the challenges posed by blood-brain interfaces surrounding the CNS, limiting the bioavailability of therapeutics. Research done over the last decade has focused on developing new strategies to overcome these limitations and successfully deliver drugs to the CNS. Nanoparticles, that are capable of encapsulating drugs with sustained drug release profiles and adjustable physiochemical properties, can cross the protective barriers surrounding the CNS. Thus, nanotechnology offers new hope for AD treatment as a strong alternative to conventional drug delivery mechanisms. In this review, the potential application of nanoparticle based approaches in Alzheimer’s disease and their implications in therapy is discussed.

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Neuropeptides in Alzheimer’s Disease: An Update

Current Alzheimer Research ◽

10.2174/1567205016666190503152555 ◽

2019 ◽

Vol 16 (6) ◽

pp. 544-558 ◽

Cited By ~ 1

Author(s):

Carla Petrella ◽

Maria Grazia Di Certo ◽

Christian Barbato ◽

Francesca Gabanella ◽

Massimo Ralli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Potential Role ◽

Brain Distribution ◽

Brain Areas ◽

Small Proteins ◽

Current Review ◽

The Central Nervous System ◽

Available Information

Neuropeptides are small proteins broadly expressed throughout the central nervous system, which act as neurotransmitters, neuromodulators and neuroregulators. Growing evidence has demonstrated the involvement of many neuropeptides in both neurophysiological functions and neuropathological conditions, among which is Alzheimer’s disease (AD). The role exerted by neuropeptides in AD is endorsed by the evidence that they are mainly neuroprotective and widely distributed in brain areas responsible for learning and memory processes. Confirming this point, it has been demonstrated that numerous neuropeptide-containing neurons are pathologically altered in brain areas of both AD patients and AD animal models. Furthermore, the levels of various neuropeptides have been found altered in both Cerebrospinal Fluid (CSF) and blood of AD patients, getting insights into their potential role in the pathophysiology of AD and offering the possibility to identify novel additional biomarkers for this pathology. We summarized the available information about brain distribution, neuroprotective and cognitive functions of some neuropeptides involved in AD. The main focus of the current review was directed towards the description of clinical data reporting alterations in neuropeptides content in both AD patients and AD pre-clinical animal models. In particular, we explored the involvement in the AD of Thyrotropin-Releasing Hormone (TRH), Cocaine- and Amphetamine-Regulated Transcript (CART), Cholecystokinin (CCK), bradykinin and chromogranin/secretogranin family, discussing their potential role as a biomarker or therapeutic target, leaving the dissertation of other neuropeptides to previous reviews.

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Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

Nature Communications ◽

10.1038/s41467-021-22301-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xin Ding ◽

Jin Wang ◽

Miaoxin Huang ◽

Zhangpeng Chen ◽

Jing Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Knock Out ◽

Classical Complement Pathway ◽

Synaptic Remodeling ◽

The Central Nervous System ◽

System Activation ◽

Knock Out Mice ◽

Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

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Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Biomolecules ◽

10.3390/biom11070980 ◽

2021 ◽

Vol 11 (7) ◽

pp. 980

Author(s):

Ka-Young Kim ◽

Ki-Young Shin ◽

Keun-A. Chang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Web Of Science ◽

Meta Analysis ◽

Cochrane Library ◽

Blood Biomarkers ◽

Cell Lineages ◽

The Central Nervous System ◽

New Biomarkers ◽

T Tau

Alzheimer’s disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new biomarkers for early diagnosis of AD. Brain-derived exosomal (BDE) proteins, which are extracellular nanovesicles released by all cell lineages of the central nervous system, have been focused as biomarkers for diagnosis, screening, prognosis prediction, and monitoring in AD. This review focused on the possibility of BDE proteins as AD biomarkers. The articles published prior to 26 January 2021 were searched in PubMed, EMBASE, Web of Science, and Cochrane Library to identify all relevant studies that reported exosome biomarkers in blood samples of patients with AD. From 342 articles, 20 studies were selected for analysis. We conducted a meta-analysis of six BDE proteins and found that levels of amyloid-β42 (standardized mean difference (SMD) = 1.534, 95% confidence interval [CI]: 0.595–2.474), total-tau (SMD = 1.224, 95% CI: 0.534–1.915), tau phosphorylated at threonine 181 (SMD = 4.038, 95% CI: 2.312-5.764), and tau phosphorylated at serine 396 (SMD = 2.511, 95% CI: 0.795–4.227) were significantly different in patients with AD compared to those in control. Whereas, those of p-tyrosine-insulin receptor substrate-1 and heat shock protein 70 did not show significant differences. This review suggested that Aβ42, t-tau, p-T181-tau, and p-S396-tau could be effective in diagnosing AD as blood biomarkers, despite the limitation in the meta-analysis based on the availability of data. Therefore, certain BDE proteins could be used as effective biomarkers for AD.

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Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

International Journal of Molecular Sciences ◽

10.3390/ijms22073330 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3330

Author(s):

Mehdi Eshraghi ◽

Aida Adlimoghaddam ◽

Amir Mahmoodzadeh ◽

Farzaneh Sharifzad ◽

Hamed Yasavoli-Sharahi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Target ◽

Neurological Disorder ◽

Inflammatory Cells ◽

Disease Pathogenesis ◽

Current Review ◽

The Brain ◽

Comprehensive Discussion

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including am-yloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

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Astrocytic transporters in Alzheimer's disease

Biochemical Journal ◽

10.1042/bcj20160505 ◽

2017 ◽

Vol 474 (3) ◽

pp. 333-355 ◽

Cited By ~ 7

Author(s):

Chris Ugbode ◽

Yuhan Hu ◽

Benjamin Whalley ◽

Chris Peers ◽

Marcus Rattray ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Neurological Diseases ◽

Current Evidence ◽

Specific Targeting ◽

Disease Modifying Therapies ◽

The Central Nervous System ◽

Disease Modifying ◽

And Function

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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