scholarly journals Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jong-Sung Park ◽  
Tae-In Kam ◽  
Saebom Lee ◽  
Hyejin Park ◽  
Yumin Oh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorders ◽  
Critical Role ◽  
Subcutaneous Administration ◽  
Reactive Astrocytes ◽  
Reactive Astrocyte ◽  
Spatial Learning And Memory ◽  
Neuronal Viability ◽  
Age Related

AbstractAlzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R+ microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders.

scholarly journals Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Priyanka Joshi ◽  
Michele Perni ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Sam Casford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unfolded Protein Response ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Unfolded Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Protein Response

AbstractAge-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.

scholarly journals Implication of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

2021 ◽  
Author(s):  
Qi Wu ◽  
Leonardo Cortez ◽  
Razieh Kamali-Jamil ◽  
Valerie Sim ◽  
Holger Wille ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Influence Function ◽  
Critical Role ◽  
Amyloid Β ◽  
Cholesterol Accumulation ◽  
Aβ Peptides ◽  
Neuronal Viability ◽  
Cultured Astrocytes ◽  
Aβ Production

Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aβ-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol level increases exosome secretion from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-CTFs, soluble APP, APP secretases and Aβ1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aβ production or by neutralizing exosomal Aβ peptide with an Aβ antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aβ peptides and influencing neuronal viability in the affected regions of the AD brain.

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.

Aluminum as a toxicant

2002 ◽  
Vol 18 (7) ◽  
pp. 309-320 ◽  
Author(s):  
A Becaria ◽  
A Campbell ◽  
SC Bondy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorders ◽  
Tissue Damage ◽  
Biological Function ◽  
Aluminum Toxicity ◽  
Microcytic Anemia ◽  
Causal Role ◽  
Dialysis Encephalopathy ◽  
Age Related

Although aluminum is the most abundant metal in nature, it has no known biological function. However, it is known that there is a causal role for aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia. Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer’s disease (AD) even though this issue is controversial. The exact mechanism of aluminum toxicity is not known but accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, eventually leading to tissue damage. This review encompasses the general toxicology of aluminum with emphasis on the potential mechanisms by which it may accelerate the progression of chronic age-related neurodegenerative disorders.

scholarly journals Structural synaptic signatures of Alzheimer's Disease and Dementia with Lewy Bodies in the male brain

2021 ◽  
Author(s):  
Oleg O. Glebov ◽  
David Williamson ◽  
Dylan M Owen ◽  
Tibor Hortobagyi ◽  
Claire Troakes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorders ◽  
Active Zone ◽  
Dementia With Lewy Bodies ◽  
Glutamate Transporter ◽  
Lewy Bodies ◽  
Age Related ◽  
The Impact

The impact of Alzheimer's Disease (AD) and Dementia with Lewy Bodies (DLB) on synaptic organisation remains poorly understood. Here, we found that in humans, DLB and AD were associated with increased synaptic levels of glutamate transporter vGlut1 and active zone protein Bassoon clustering respectively; these effects were only observed in male brain samples. These findings demonstrate disease- and sex-specific presynaptic structural remodelling in age-related neurodegenerative disorders.

scholarly journals ALZHEIMER’S DISEASE: A CONSEQUENCE OF IMPAIRED MITOPHAGY?

2019 ◽  
pp. 75-80
Author(s):  
VIVEK SHARMA
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Proper Function ◽  
Neuronal Viability ◽  
Cellular Energy ◽  
Mitochondrial Homeostasis ◽  
Neuronal Homeostasis ◽  
Age Related ◽  
Characteristic Features

Neurodegenerative disorders involve complexities of the pathologies, characterized by the progressive loss of neuronal viability, leading to severe physical and cognitive impairments in affected patients. These disorders although may differ in clinical outcomes yet they share common features such as aggregation of neurotoxic metabolites and perturbed cellular and neuronal homeostasis. Mitochondrion is an indispensable organelle for neuronal survival, and its role and place have become critical in research arena of aging and neurodegenaration. The accumulation of damaged mitochondria has been linked to normal aging and multiple age-related disorders including Alzheimer’s disease (AD). Survival and proper function of mitochondria depend on several attributes that include mitochondrial biogenesis and fusion and fission. Mitophagy is an utmost requirement for degradation and removal of damaged mitochondria where the target mitochondria are identified by the autophagosomes and delivered to the lysosome for degradation. Mitophagy plays important roles in mitochondrial homeostasis, neuroprotection, and resistance to neurodegeneration. AD besides other characteristic features involves mitochondrial dysfunctional, bioenergetic deficit, and altered mitophagy. The autophagy/lysosome pathway that removes damaged mitochondria (mitophagy) is compromised in AD, resulting in the accumulation of dysfunctional mitochondria that contribute to synaptic dysfunction and cognitive deficits by triggering Aβ and Tau accumulation through increases in oxidative damage and cellular energy deficits. The present work reviews the various implications of mitophagy in relevance to the pathology of AD.

scholarly journals The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer’s Disease

2020 ◽  
Vol 13 ◽  
pp. 117864692097265
Author(s):  
FJH Sorgdrager ◽  
CP van Der Ley ◽  
M van Faassen ◽  
E Calus ◽  
EA Nollen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Spatial Learning And Memory ◽  
Behavioral Deficits ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Pathway Activation ◽  
Metabolite Profiles

Alzheimer’s disease (AD) is associated with progressive endogenous neurotoxicity and hampered inflammatory regulation. The kynurenine (Kyn) pathway, which is controlled by tryptophan 2,3-dioxygenase (TDO), produces neuroactive and anti-inflammatory metabolites. Age-related Kyn pathway activation might contribute to AD pathology in humans, and inhibition of TDO was found to reduce AD-related cellular toxicity and behavioral deficits in animal models. To further explore the effect of aging on the Kyn pathway in the context of AD, we analyzed Kyn metabolite profiles in serum and brain tissue of the APP23 amyloidosis mouse model. We found that aging had genotype-independent effects on Kyn metabolite profiles in serum, cortex, hippocampus and cerebellum, whereas serum concentrations of many Kyn metabolites were reduced in APP23 mice. Next, to further establish the role of TDO in AD-related behavioral deficits, we investigated the effect of long-term pharmacological TDO inhibition on cognitive performance in APP23 mice. Our results indicated that TDO inhibition reversed recognition memory deficits without producing measurable changes in cerebral Kyn metabolites. TDO inhibition did not affect spatial learning and memory or anxiety-related behavior. These data indicate that age-related Kyn pathway activation is not specific for humans and could represent a cross-species phenotype of aging. These data warrant further investigation on the role of peripheral Kyn pathway disturbances and cerebral TDO activity in AD pathophysiology.

scholarly journals S-nitrosylation-impaired autophagy: An alternative mechanism underlying aging?

2013 ◽  
Author(s):  
Qing-Ping Zeng
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorders ◽  
Alternative Mechanism ◽  
Age Related ◽  
Surprising Finding

Aging is mysterious with unknown managing patterns. A surprising finding on the tune mode of autophagy by S-nitrosylation is a distinctive step towards the interpretation of the mechanism underlying aging and age-related diseases. This commentary article will discuss, in a wider sense, the implications of S-nitrosylation- and nitration-switched dysfunction of proteins/enzymes in neurodegenerative disorders including Alzheimer's disease (AD), Huntington's diseases (HD) and Parkinson's disease (PD).

scholarly journals S-nitrosylation-impaired autophagy: An alternative mechanism underlying aging?

2013 ◽  
Author(s):  
Qing-Ping Zeng
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorders ◽  
Alternative Mechanism ◽  
Age Related ◽  
Surprising Finding

Aging is mysterious with unknown managing patterns. A surprising finding on the tune mode of autophagy by S-nitrosylation is a distinctive step towards the interpretation of the mechanism underlying aging and age-related diseases. This commentary article will discuss, in a wider sense, the implications of S-nitrosylation- and nitration-switched dysfunction of proteins/enzymes in neurodegenerative disorders including Alzheimer's disease (AD), Huntington's diseases (HD) and Parkinson's disease (PD).

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