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

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: March 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.

Language: Английский

---

Cellular Senescence in Brain Aging

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: Feb. 25, 2021

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in structural plasticity dendritic spines. Decreased number maturity spines aged animals humans, together synaptic transmission, may reflect aberrant neuronal directly associated impaired functions. In extreme, neurodegenerative disease, completely devastates basic functions brain, develop. While cellular senescence peripheral tissues recently linked aging aging-related disorders, its involvement is just beginning be explored. However, accumulated evidence suggests that cell play role it documented other organs. Senescent cells stop dividing shift their activity strengthen secretory function, leads acquisition so called senescence-associated phenotype (SASP). have also characteristics, such altered morphology proteostasis, decreased propensity undergo apoptosis, autophagy impairment, accumulation lipid droplets, increased senescence-associated-β-galactosidase (SA-β-gal), epigenetic alterations, including DNA methylation, chromatin remodeling, histone post-translational modifications that, consequence, result gene expression. Proliferation-competent glial both vitro vivo , they likely participate neuroinflammation, characteristic for brain. apart from proliferation-competent cells, consists post-mitotic neurons. Interestingly, emerged recently, non-proliferating present or cultivated some hallmarks, SASP, typical senescent ceased divide. It senolytics, by definition, eliminate improve ability mice models. this review, we ask questions about impairments how senolytics them. We will discuss whether plasticity, defined morphological functional at level neurons spines, hallmark susceptible effects senolytics.

Language: Английский

---

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

Journal of Neurochemistry, Journal Year: 2019, Volume and Issue: 151(6), P. 676 - 688

Published: Sept. 3, 2019

The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer's disease is increased age. Therefore, understanding the changes that occur as a result aging central to any possible prevention or cure such conditions. Microglia, resident brain glial population most associated with both protection neurons in health and their destruction disease, could be significant player age related changes. Microglia can adopt an aberrant phenotype sometimes referred either dystrophic senescent. While aged microglia have been frequently identified there no conclusive evidence proves causal role. This has hampered by lack models microglia. We recently generated model senescent based on observation all show iron overload. Iron-overloading cultured causes them take cause neurodegeneration similar those observed patients. review considers how this used determine role diseases.

Language: Английский

---

Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain

GeroScience, Journal Year: 2020, Volume and Issue: 42(2), P. 429 - 444

Published: March 31, 2020

Language: Английский

---

Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia

Cell Reports, Journal Year: 2021, Volume and Issue: 36(3), P. 109419 - 109419

Published: July 1, 2021

Language: Английский

---

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Journal of Neuroinflammation, Journal Year: 2021, Volume and Issue: 18(1)

Published: Jan. 22, 2021

Age-related macular degeneration (AMD), a degenerative disease in the central macula area of neuroretina and supporting retinal pigment epithelium, is most common cause vision loss elderly. Although advances have been made, treatment to prevent progressive lacking. Besides association innate immune pathway genes with AMD susceptibility, environmental stress- cellular senescence-induced alterations pathways such as metabolic functions inflammatory responses are also implicated pathophysiology AMD. Cellular senescence an adaptive cell process response noxious stimuli both mitotic postmitotic cells, activated by tumor suppressor proteins prosecuted via secretome. In addition physiological roles embryogenesis tissue regeneration, augmented age contributes variety age-related chronic conditions. Accumulation senescent cells accompanied impairment immune-mediated elimination mechanisms results increased frequency termed "chronic" senescence. Age-associated exhibit abnormal metabolism, generation reactive oxygen species, heightened senescence-associated secretory phenotype that nurture proinflammatory milieu detrimental neighboring cells. Senescent changes various choroidal including microglia, neurons, endothelial contemporaneous systemic aging emerged important contributors onset development The repertoire senotherapeutic strategies senolytics, senomorphics, cycle regulation, restoring homeostasis targeted at levels expanding potential treat spectrum diseases,

Language: Английский

---

Loss of lamin‐B1 and defective nuclear morphology are hallmarks of astrocyte senescence in vitro and in the aging human hippocampus

Aging Cell, Journal Year: 2021, Volume and Issue: 21(1)

Published: Dec. 10, 2021

The increase in senescent cells tissues, including the brain, is a general feature of normal aging and age-related pathologies. Senescent exhibit specific phenotype, which includes an altered nuclear morphology transcriptomic changes. Astrocytes undergo senescence vitro age-associated neurodegenerative diseases, but little known about whether this process also occurs physiological aging, as well its functional implication. Here, we investigated astrocyte vitro, old mouse brains, post-mortem human brain tissue elderly. We identified significant loss lamin-B1, major component lamina, hallmark astrocytes. showed severe reduction lamin-B1 dentate gyrus aged mice, hippocampal astrocytes, granular cell layer hippocampus from non-demented was associated with deformations, represented by increased incidence invaginated nuclei circularity astrocytes hippocampus. found differences levels between polymorphic elderly hippocampus, suggesting intra-regional-dependent response Moreover, described senescence-associated impaired neuritogenic synaptogenic capacity Our findings show that conserved shed light on defects lamina structure may contribute to dysfunctions during aging.

Language: Английский

---

Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 1869 - 1869

Published: Jan. 18, 2023

Aging is the most prominent risk factor for late-onset Alzheimer’s disease. associates with a chronic inflammatory state both in periphery and central nervous system, evidence thereof mechanisms leading to neuroinflammation being discussed. Nonetheless, significantly enhanced by accumulation of amyloid beta accelerates progression disease through various pathways discussed present review. Decades clinical trials targeting 2 abnormal proteins disease, tau, led many failures. As such, via different strategies could prove valuable therapeutic strategy, although much research still needed identify appropriate time window. Active focusing on identifying early biomarkers help translating these novel from bench bedside.

Language: Английский

---

P16INK4A—More Than a Senescence Marker

Life, Journal Year: 2022, Volume and Issue: 12(9), P. 1332 - 1332

Published: Aug. 28, 2022

Aging is a biological feature that characterized by gradual degeneration of function in cells, tissues, organs, or an intact organism due to the accumulation environmental factors and stresses with time. Several have been attributed aging such as oxidative stress augmented production exposure reactive oxygen species, inflammatory cytokines production, telomere shortening, DNA damage, and, importantly, deposit senescent cells. These are irreversibly mitotically inactive, yet metabolically active The reason underlying their senescence lies within extrinsic intrinsic arms. arm mainly expression secretory profile known senescence-associated phenotype (SASP). results from impact several genes meant regulate cell cycle, tumor suppressor genes. P16

Language: Английский

---

Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging

Life Medicine, Journal Year: 2022, Volume and Issue: 1(2), P. 103 - 119

Published: Aug. 9, 2022

Abstract Aging is a natural but relentless process of physiological decline, leading to physical frailty, reduced ability respond stresses (resilience) and, ultimately, organismal death. Cellular senescence, self-defensive mechanism activated in response intrinsic stimuli and/or exogenous stress, one the central hallmarks aging. Senescent cells cease proliferate, while remaining metabolically active and secreting numerous extracellular factors, feature known as senescence-associated secretory phenotype. Senescence physiologically important for embryonic development, tissue repair, wound healing, prevents carcinogenesis. However, chronic accumulation persisting senescent contributes host pathologies including age-related morbidities. By paracrine endocrine mechanisms, can induce inflammation locally systemically, thereby causing dysfunction, organ degeneration. Agents those targeting damaging components phenotype or inducing apoptosis exhibit remarkable benefits both preclinical models early clinical trials geriatric conditions. Here we summarize features outline strategies holding potential be developed interventions. In long run, there an increasing demand safe, effective, clinically translatable senotherapeutics address healthcare needs current settings global

Language: Английский

---