Hippocampus and its involvement in Alzheimer’s disease: a review

3 Biotech, Год журнала: 2022, Номер 12(2)

Опубликована: Фев. 1, 2022

Hippocampus is the significant component of limbic lobe, which further subdivided into dentate gyrus and parts Cornu Ammonis. It crucial region for learning memory; its sub-regions aid in generation episodic memory. However, hippocampus one brain areas affected by Alzheimer's (AD). In early stages AD, shows rapid loss tissue, associated with functional disconnection other brain. progression atrophy medial temporal hippocampal regions are structural markers magnetic resonance imaging (MRI). Lack sirtuin (SIRT) expression neurons will impair cognitive function, including recent memory spatial learning. Proliferation, differentiation, migrations steps involved adult neurogenesis. The microglia more immunologically active than Intrinsic factors like hormones, glia, vascular nourishment instrumental neural stem cell (NSC) functions maintaining brain's microenvironment. Along intrinsic factors, many extrinsic dietary intake physical activity may also influence NSCs. Hence, pro-neurogenic lifestyle could delay neurodegeneration.

Язык: Английский

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A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

Frontiers in Immunology, Год журнала: 2020, Номер 11

Опубликована: Март 31, 2020

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout AD its continuum. Large-scale genome-wide association studies point out several genetic variants - TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, HLA-DRB5-HLA-DRB1 potentially linked to neuroinflammation. Most these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins cell turn-over, synaptic activity, lipid metabolism, vesicle trafficking. Proteomic indicate that a plethora interconnected aberrant molecular pathways, set off perpetuated by TNF-α, TGF-β, IL-1β, receptor protein Microglia astrocytes key cellular drivers regulators Under physiological conditions, they important for neurotransmission homeostasis. In AD, there is turning pathophysiological evolution where glial cells sustain an overexpressed inflammatory response synergizes with amyloid-β tau accumulation, drives synaptotoxicity neurodegeneration self-reinforcing manner. Despite strong therapeutic rationale, previous trials investigating compounds anti-inflammatory properties, including non-steroidal drugs (NSAIDs) did not achieve primary efficacy endpoints. It conceivable study design issues, lack diagnostic accuracy biomarkers target population identification proof-of-mechanism may partially explain negative outcomes. However, recent meta-analysis indicates potential biological effect NSAIDs. this regard, candidate fluid neuroinflammation under analytical/clinical validation, i.e. MCP-1, IL-6, TNF-α complexes, YKL-40. PET radio-ligands investigated accomplish in-vivo longitudinal regional exploration Biomarkers tracking different pathways (body matrixes) along brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between other mechanisms. Robust biomarker-drug co-development pipelines expected enrich large-scale testing new-generation active, directly or indirectly, on targets displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), AL003 (anti-CD33 antibody). As next step, taking advantage breakthrough multimodal techniques coupled systems biology approach path pursue developing individualized strategies targeting framework precision medicine.

Язык: Английский

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Insulin and Insulin Resistance in Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(18), С. 9987 - 9987

Опубликована: Сен. 15, 2021

Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates transport into cells and suppresses hepatic production. influences cell growth, differentiation protein synthesis, inhibits catabolic processes such glycolysis, lipolysis proteolysis. insulin-like growth factor-1 receptors are expressed on all types the central nervous system. Widespread distribution brain confirms that insulin signaling important diverse this organ. is known to regulate support cognition, enhance outgrowth neurons, modulate release uptake catecholamine, expression localization gamma-aminobutyric acid (GABA). also able freely cross blood–brain barrier from circulation. In addition, changes signaling, caused inter alia resistance, may accelerate aging, affect plasticity possibly neurodegeneration. There two significant signal transduction pathways: PBK/AKT pathway which responsible for metabolic effects, MAPK survival gene expression. The aim study describe role played by CNS, both healthy people those with pathologies resistance Alzheimer’s disease.

Язык: Английский

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Microglial phagocytosis of neurons in neurodegeneration, and its regulation

Journal of Neurochemistry, Год журнала: 2021, Номер 158(3), С. 621 - 639

Опубликована: Фев. 20, 2021

There is growing evidence that excessive microglial phagocytosis of neurons and synapses contributes to multiple brain pathologies. RNA-seq genome-wide association (GWAS) studies have linked phagocytic genes neurodegenerative diseases, knock-out has been found protect against neurodegeneration in animal models, suggesting neurodegeneration. Here, we review recent live causes models Alzheimer's disease other tauopathies, Parkinson's disease, frontotemporal dementias, sclerosis, retinal degeneration induced by ischaemia, infection or ageing. We also factors regulating neurons, including: nucleotides, frackalkine, phosphatidylserine, calreticulin, UDP, CD47, sialylation, complement, galectin-3, Apolipoprotein E, receptors, Siglec cytokines, epigenetics expression profile. Some these may be potential treatment targets prevent mediated synapses.

Язык: Английский

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Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease

Stem Cells Translational Medicine, Год журнала: 2020, Номер 9(9), С. 1068 - 1084

Опубликована: Июнь 4, 2020

The critical role of neuroinflammation in favoring and accelerating the pathogenic process Alzheimer's disease (AD) increased need to target cerebral innate immune cells as a potential therapeutic strategy slow down progression. In this scenario, mesenchymal stem (MSCs) have risen considerable interest thanks their immunomodulatory properties, which been largely ascribed release extracellular vesicles (EVs), namely exosomes microvesicles. Indeed, beneficial effects MSC-EVs regulating inflammatory response reported different AD mouse models, upon chronic intravenous or intracerebroventricular administration. study, we use triple-transgenic 3xTg mice showing for first time that intranasal route administration EVs, derived from cytokine-preconditioned MSCs, was able induce neuroprotective AD. reached brain, where they dampened activation microglia dendritic spine density. polarized vitro murine primary toward an anti-inflammatory phenotype suggesting observed transgenic could result positive modulation status. possibility administer through noninvasive demonstration efficacy might accelerate chance translational exploitation

Язык: Английский

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Shaping Neuronal Fate: Functional Heterogeneity of Direct Microglia-Neuron Interactions

Neuron, Год журнала: 2020, Номер 109(2), С. 222 - 240

Опубликована: Дек. 2, 2020

Язык: Английский

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Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model

Molecular Neurodegeneration, Год журнала: 2021, Номер 16(1)

Опубликована: Март 22, 2021

Abstract Background Recent studies suggest that microglia contribute to tau pathology progression in Alzheimer’s disease. Amyloid plaque accumulation transforms microglia, the primary innate immune cells brain, into neurodegenerative (MGnD), which exhibit enhanced phagocytosis of plaques, apoptotic neurons and dystrophic neurites containing aggregated phosphorylated (p-tau). It remains unclear how promote disease while actively phagocytosing pathological proteins, therefore ameliorating pathology. Methods Adeno-associated virus expressing P301L mutant (AAV-P301L-tau) was stereotaxically injected medial entorhinal cortex (MEC) C57BL/6 (WT) humanized APP knock-in homozygote ( App NL-G-F ) mice at 5 months age. Mice were fed either chow a colony stimulating factor-1 receptor inhibitor (PLX5622) or control from 4 6 age test effect depletion. Animals tested for immunofluorescence, biochemistry, FACS microglia. In order monitor microglial extracellular vesicle secretion vivo, novel lentiviral EV reporter system engineered express mEmerald-CD9 (mE-CD9) specifically same region MEC. Results Expressing MEC induced propagation granule cell layer hippocampal dentate gyrus, significantly exacerbated compared WT mice. Administration PLX5622 depleted nearly all mouse brains dramatically reduced p-tau greater extent mice, although it increased burden plaque-associated + neurites. Plaque-associated MGnD strongly expressed an marker, tumor susceptibility gene 101, indicative heightened synthesis EVs. Intracortical injection mE-CD9 lentivirus successfully microglia-specific expression particles, Mac2 − homeostatic Finally, consecutive intracortical AAV-P301L-tau revealed encapsulation EVs as determined by super-resolution microscopy immuno-electron microscopy. Discussion Our findings hyper-secrete compacting Aβ plaques clearing NP tau, we propose mechanistic link between amyloid deposition exacerbation

Язык: Английский

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Microglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission

Seminars in Cell and Developmental Biology, Год журнала: 2019, Номер 94, С. 138 - 151

Опубликована: Май 30, 2019

Язык: Английский

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Neuroimmune Connections in Aging and Neurodegenerative Diseases

Trends in Immunology, Год журнала: 2020, Номер 41(4), С. 300 - 312

Опубликована: Март 9, 2020

Язык: Английский

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Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis

Alzheimer s & Dementia, Год журнала: 2022, Номер 18(11), С. 2327 - 2340

Опубликована: Март 2, 2022

Abstract Objective Evaluating the efficacy of 3,6’‐dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test hypothesis that neuroinflammation is directly involved development synaptic/neuronal loss and cognitive decline. Background Amyloid‐β (Aβ) or tau‐focused clinical trials have proved unsuccessful mitigating AD‐associated impairment. Identification new drug targets needed. Neuroinflammation a therapeutic target neurodegenerative disorders, TNF‐α pivotal neuroinflammatory driver. New chronic drives progressive Pharmacologically microglial/astrocyte activation without altering Aβ generation will define role AD progression. Major challenges Difficulty TNF‐α‐lowering compounds reaching brain, identification therapeutic‐time window preserve beneficial processes. Linkage other major theories Microglia/astroglia are heavily implicated maintenance synaptic plasticity/function healthy brain disrupted by Aβ. Mitigation gliosis can restore homeostasis/cognitive function.

Язык: Английский

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