Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease

Kaur, Darshpreet; Sharma, Vivek; Deshmukh, Rahul

doi:10.1007/s10787-019-00580-x

Cited by 301 publications

(205 citation statements)

References 169 publications

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“…Microglia, resident macrophages of the neurological system, act as a defense mechanism for the central nervous system. Together with astrocytes, they create a mesh of activity that leads to inflammation and the progression of AD [78,79]. In our study, we have shown a reduction in both these neurological hallmarks through immunohistochemistry, which leads us to believe that caspase-6 has a direct effect on microglia and astrocyte activation in this mouse model of AD.…”

Section: Discussionsupporting

confidence: 57%

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

Angel

Volkman

Royal

et al. 2020

IJMS

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-β plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD. cleavage into smaller subunits that form the active caspase heterodimer [6]. Caspases have been implicated in numerous diseases as their function leads to apoptosis and cell death [7,8]. Elucidating their roles in those diseases has been the subject of many years of research around the world.Caspase-6 belongs to the pro-apoptotic executioner caspase group and is activated by a series of upstream activators, amongst which are caspase-3 and caspase-1 [9,10]. Caspase-6 was shown to mediate several non-apoptotic processes, such as facilitating axonal pruning during development [11,12]. Cleavage by caspase-6 of the mutant huntingtin gene was shown to be a prerequisite for neuronal dysfunction and degeneration, and therefore, exacerbates neurodegeneration in Huntington's disease [8,13]. Caspase-6 activity is associated with AD pathological lesions and is present at the early stages of tangle formation [14]. The pro-apoptotic protein p53 is increased in AD brains and p53 directly up-regulates the transcription of caspase-6 [15], resulting in a significant increase in caspase-6 mRNA in human AD brains. Caspase-6 cleaves the APP at a specific site, creating the toxic small peptide C31, a potent inducer of apoptosis in cultured neuroblastoma cells [4]. Thus, caspase-6 is considered to be an up-stream modulator of AD pathogenesis, and as a result, a viable therapeutic target for the treatment of AD [8].Caspase-6 knock-out (KO) neurons are protected against excitotoxicity, trophic factor deprivation, and myelin induced axonal degeneration [16]. Caspase-6 KO mice were first described by Uribe et al. [16]. Research using these mice showed a reduction in the inflammatory response and...

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Section: Discussionsupporting

confidence: 57%

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

Angel

Volkman

Royal

et al. 2020

IJMS

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“…Moreover, reactive astrocytes acquire gain of toxic function and exhibits neurotoxic effects with loss of neurotrophic functions. The dysfunction in the astrocytes results in increased release of cytokines and inflammatory mediators, neurodegeneration, decreased glutamate uptake, loss of neuronal synapses, and ultimately cognitive deficit …”

Section: Signaling Of Astroglial Inos and Neuroinflammationmentioning

confidence: 99%

“…The dysfunction in the astrocytes results in increased release of cytokines and inflammatory mediators, neurodegeneration, decreased glutamate uptake, loss of neuronal synapses, and ultimately cognitive deficit. [34] Unlike nNOS and eNOS, activation of iNOS is tightly associated with its expression levels. Several mechanisms are involved in the regulation of iNOS expression in glial cells and this regulation is mainly present at the transcriptional level.…”

Section: Signaling Of Astroglial Inos and Neuroinflammationmentioning

confidence: 99%

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

et al. 2020

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Gliomas are the most prevalent primary tumors of the brain and spinal cord. Histologically, they share features of normal glial cells, but whether gliomas originate from normal glial cells, glial or neural precursors, stem cells, or other cell types remains a topic of investigation. The enhanced expression of inducible nitric oxide synthase (iNOS) has been reported as a hallmark of chemoresistance in gliomas, and several lines of evidence have reported that a decreased proliferation of glioma cells could be related to the selective inhibition of iNOS. This review aims to summarize the current understanding of iNOS expression and activity modulation in the regulation of glioma pathogenesis, along with compounds that could act as therapeutic agents against glioma.

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“…Aβ pathology Aβ could damage synaptic junction and generate neurovirulence, and destroy intracellular calcium homeostasis and cholinergic nerve system, inducing neurofibrillary tangles, and so forth [5][6][7] Tau pathology Tau aggregates impair axonal transport, mitochondrial function, and cytoskeletal dynamics and elevate oxidative stress 7,8 Oxidative stress The increased production of ROS damages the mitochondrial function, alters metal homeostasis, reduces the antioxidant defense, and directly affects synaptic activity and neurotransmission in neurons leading to cognitive dysfunction [9][10][11] Inflammation Neuroinflammation results in increased release of cytokines and inflammatory mediators such as IL-1β, IL-6, and TNF-α, neurodegeneration, decreased glutamate uptake, loss of neuronal synapses, increased levels of ROS, and ultimately cognitive deficits [12][13][14] Cholinergic neuron degeneration…”

Section: Hypothesis Mechanisms Referencesmentioning

confidence: 99%

“…While nearly 95% of patients with AD are classified as sAD, which are caused by a combination of genetic factors and environmental risk factors without documented familial history of AD . Various hypotheses of mechanisms for sAD include deposition of β‐amyloid (Aβ), hyperphosphorylation of Tau, oxidative stress, neuroinflammation, cholinergic neuron degeneration, gut microbiota disorders, lipid metabolism abnormalities, autophagy dysfunction, insulin desensitization/resistance state, synapse dysfunction, and metal ions disorders in the brain (summarized in Table ).…”

Section: Introductionmentioning

confidence: 99%

Advance of sporadic Alzheimer's disease animal models

Zhang

Chen

Mak

et al. 2019

Medicinal Research Reviews

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Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disease. In the past decades, numbers of promising drug candidates showed significant anti‐AD effects in preclinical studies but failed in clinical trials. One of the major reasons might be the limitation of appropriate animal models for evaluating anti‐AD drugs. More than 95% of AD cases are sporadic AD (sAD). However, the anti‐AD drug candidates were mainly tested in the familial AD (fAD) animal models. The diversity between the sAD and fAD might lead to a high failure rate during the development of anti‐AD drugs. Therefore, an ideal sAD animal model is urgently needed for the development of anti‐AD drugs. Here, we summarized the available sAD animal models, including their methodology, pathologic features, and potential underlying mechanisms. The limitations of these sAD animal models and future trends in the field were also discussed.

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Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease

Cited by 301 publications

References 169 publications

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

Advance of sporadic Alzheimer's disease animal models

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