Hallmarks of neurodegenerative diseases

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

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Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

Frontiers in Aging Neuroscience, Год журнала: 2021, Номер 13

Опубликована: Фев. 18, 2021

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly response to external insults metabolic status via fission fusion (so-called mitochondrial dynamics) that maintain quality homeostasis. Damaged mitochondria removed by process known as mitophagy, involves their degradation specific autophagosomal pathway. Over last few years, remarkable efforts have been made investigate impact on pathogenesis of Alzheimer's disease (AD) various forms dysfunction, such excessive reactive oxygen species (ROS) production, Ca2+ dyshomeostasis, loss ATP, defects dynamics transport, mitophagy. Recent research suggests restoration function physical exercise, an antioxidant diet, or therapeutic approaches can delay onset slow progression AD. In this review, we focus recent progress highlights crucial alterations oxidative stress AD, emphasizing framework existing potential approaches.

Язык: Английский

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Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(22), С. 8767 - 8767

Опубликована: Ноя. 20, 2020

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source brain. The brain’s utilization of ketones seems to depend mainly on concentration blood, thus many dietary approaches such as ketogenic diets, ingestion medium-chain fatty acids or exogenous ketones, facilitate significant changes metabolism. Therefore, these may ameliorate crisis neurodegenerative diseases, which are characterized by a deterioration metabolism, providing therapeutic advantage diseases. Most clinical studies examining neuroprotective role have been conducted patients with Alzheimer’s disease, imaging support notion enhancing metabolism ketones. Likewise, few show modest functional improvements Parkinson’s disease and cognitive benefits with—or at risk of—Alzheimer’s after interventions. Here, we summarize current knowledge how interventions discuss emphasizing data.

Язык: Английский

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Astrocyte-neuron metabolic cooperation shapes brain activity

Cell Metabolism, Год журнала: 2021, Номер 33(8), С. 1546 - 1564

Опубликована: Авг. 1, 2021

Язык: Английский

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Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration

Neuropharmacology, Год журнала: 2021, Номер 196, С. 108719 - 108719

Опубликована: Июль 15, 2021

Glutamate is the primary excitatory neurotransmitter of brain. Cellular homeostasis glutamate paramount importance for normal brain function and relies on an intricate metabolic collaboration between neurons astrocytes. extensively recycled astrocytes in a process known as glutamate-glutamine cycle. The recycling closely linked to energy metabolism essential sustain glutamatergic neurotransmission. However, considerable amount also metabolized serves hub connecting glucose amino acid both Disruptions clearance, leading neuronal overstimulation excitotoxicity, have been implicated several neurodegenerative diseases. Furthermore, link gaining attention neurological conditions. In this review, we provide overview dynamics synaptic underlying processes with cellular focus particular, review recently discovered role uptake discuss current advances context Alzheimer's disease Huntington's disease. Understanding regulation glutamate-dependent at synapse will not only increase our insight into mechanisms homeostasis, but may reveal new targets ameliorate neurodegeneration. This article part Neuropharmacology Special Issue 'Glutamate Receptors - Glutamatergic Synapse'.

Язык: Английский

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Association Between Age at Diabetes Onset and Subsequent Risk of Dementia

JAMA, Год журнала: 2021, Номер 325(16), С. 1640 - 1640

Опубликована: Апрель 27, 2021

Importance

Trends in type 2 diabetes show an increase prevalence along with younger age of onset. While vascular complications early-onset are known, the associations dementia remains unclear.

Objective

To determine whether at onset is more strongly associated incidence dementia.

Design, Setting, and Participants

Population-based study UK, Whitehall II prospective cohort study, established 1985-1988, clinical examinations 1991-1993, 1997-1999, 2002-2004, 2007-2009, 2012-2013, 2015-2016, linkage to electronic health records until March 2019. The date final follow-up was 31,

Exposures

Type diabetes, defined as a fasting blood glucose level greater than or equal 126 mg/dL examination, physician-diagnosed use medication, hospital record between 1985

Main Outcomes Measures

Incident ascertained through records.

Results

Among 10 095 participants (67.3% men; aged 35-55 years 1985-1988), total 1710 cases 639 were recorded over median 31.7 years. Dementia rates per 1000 person-years 8.9 without 70 years, 10.0 for up 5 earlier, 13.0 6 18.3 earlier. In multivariable-adjusted analyses, compared 70, hazard ratio (HR) earlier 2.12 (95% CI, 1.50-3.00), 1.49 0.95-2.32) 1.11 0.70-1.76) less; linear trend test (P < .001) indicated graded association At every 5-year significantly HR 1.24 1.06-1.46) analyses adjusted sociodemographic factors, behaviors, health-related measures.

Conclusions Relevance

this longitudinal higher risk subsequent

Язык: Английский

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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Язык: Английский

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Mitochondrial dysfunction: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 15, 2024

Abstract Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation disease progression. Particularly, mitochondrial dysfunctions identified many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, cancer. However, the multifaceted nature elusive phenotypic threshold dysfunction complicate our understanding contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among most important therapeutic targets. In recent years, strategies targeting have continuously emerged transitioned clinical trials. Advanced intervention such as using healthy replenish or replace damaged mitochondria, has shown promise preclinical trials various Mitochondrial components, mtDNA, mitochondria-located microRNA, associated proteins can be potential agents augment function immunometabolic diseases tissue injuries. Here, we review current knowledge pathophysiology concrete examples We also summarize treat perspective dietary supplements targeted therapies, well translational situation related pharmacology agents. Finally, this discusses innovations applications transplantation an advanced promising treatment.

Язык: Английский

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Biomarkers of aging

Science China Life Sciences, Год журнала: 2023, Номер 66(5), С. 893 - 1066

Опубликована: Апрель 11, 2023

Язык: Английский

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Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

FEBS Journal, Год журнала: 2022, Номер 290(6), С. 1420 - 1453

Опубликована: Янв. 8, 2022

Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, a lack of disease‐modifying therapeutics. While the abnormal accumulation lipids was described in very first report AD neuropathology, it not until recent decades that lipid dyshomeostasis became focus research. Clinically, lipidomic metabolomic studies have consistently shown alterations levels various classes emerging early stages brains. Mechanistically, discovery research revealed multifaceted interactions between metabolism key pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, myelin degeneration. In present review, converging evidence defining summarized, followed by discussions on which contributes to pathogenesis modifies risk. Furthermore, lipid‐targeting therapeutic strategies, modification their efficacy stage, ApoE status, metabolic vascular profiles, are reviewed.

Язык: Английский

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