KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury.

Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.

Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases.

Presenilin, a transmembrane protein primarily known for its role in Alzheimer's disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin's diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aß42-to-Aß40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin's involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease.

The multifaceted functions of ß-arrestins and their therapeutic potential in neurodegenerative diseases.

Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, ß-arrestin1, ß-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of ß-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that ß-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). ß-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, ß-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, ß-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the ß2AR regulates SNCA gene expression. In this review, we aim to provide an overview of ß-arrestin1 and ß-arrestin2, and describe their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of ß-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets.

A comprehensive review on therapeutic potentials of photobiomodulation for neurodegenerative disorders.

A series of experimental trials over the past two centuries has put forth Photobiomodulation (PBM) as a treatment modality that utilizes colored lights for various conditions. While in its cradle, PBM was used for treating simple conditions such as burns and wounds, advancements in recent years have extended the use of PBM for treating complex neurodegenerative diseases (NDDs). PBM has exhibited the potential to curb several symptoms and signs associated with NDDs. While several of the currently used therapeutics cause adverse side effects alongside being highly invasive, PBM on the contrary, seems to be broad-acting, less toxic, and non-invasive. Despite being projected as an ideal therapeutic for NDDs, PBM still isn't considered a mainstream treatment modality due to some of the challenges and knowledge gaps associated with it. Here, we review the advantages of PBM summarized above with an emphasis on the common mechanisms that underlie major NDDs and how PBM helps tackle them. We also discuss important questions such as whether PBM should be considered a mainstay treatment modality for these conditions and if PBM's properties can be harnessed to develop prophylactic therapies for high-risk individuals and also highlight important animal studies that underscore the importance of PBM and the challenges associated with it. Overall, this review is intended to bring the major advances made in the field to the spotlight alongside addressing the practicalities and caveats to develop PBM as a major therapeutic for NDDs.

An overview of systematic reviews of acupuncture for neurodegenerative disease.

BACKGROUND: Acupuncture has been widely used in the treatment of neurodegenerative diseases and a large number of systematic reviews (SRs) have been published, but the results are controversial. Therefore, it is necessary to comprehensively summarize and objectively evaluate the clinical evidence of acupuncture for neurodegenerative diseases. OBJECTIVE: To evaluate the SRs that assess the efficacy and safety of acupuncture for neurodegenerative diseases. This overview is intended to provide evidence for clinical decision making by healthcare providers and policymakers and to provide evidence for clinical decision making by healthcare providers and policymakers and to provide recommendations for researchers to conduct high quality SRs and clinical studies. METHODS: We searched four Chinese databases (SinoMed, CNKI, Wanfang and VIP) and four international databases (Cochrane Library, Embase, PubMed and Web of Science) for SRs of acupuncture for neurodegenerative diseases. The search period ran from the beginning of the database to March 5, 2023. Literature screening and data extraction were performed independently by two individuals. Methodological quality, risk of bias and associated evidence levels were assessed for all SRs using AMSTER 2, ROBIS and GRADE tools. In addition, the RCT overlap between SRs was calculated by corrected coverage area (CCA). We also conducted quantitative synthesis or descriptive analysis of the relevant data. RESULTS: Finally, we identified 53 SRs (three were qualitative descriptions and fifty were meta-analyses). Under AMSTAR 2, only one SR was rated as moderate quality, six SRs as low quality and 46 SRs as very low quality. According to ROBIS, 33 SRs were rated as a high risk of bias and 20 as a low risk of bias. Cognitive functions in neurodegenerative diseases, activities of daily living and the motor and non-motor outcomes associated with PD were included to summary description. The pooled results show that acupuncture combined with conventional treatment may have an overall advantage over conventional treatment, but the quality of evidence is low. Specific adverse reactions/events were reported in 20 SRs. Common needle-related adverse events included pain, dizziness, bleeding, or subcutaneous hematoma. No severe adverse events were reported in any SRs. CONCLUSION: Evidence suggests that acupuncture is generally effective and relatively safe for cognitive function and activities of daily living in neurodegenerative diseases. In addition, acupuncture may have some benefits in improving motor and non-motor symptoms in patients with PD. However, high-quality RCTs and SRs are still needed to further clarify the efficacy and safety of acupuncture in treating neurodegenerative diseases.

The bioaccessibility of adsorped heavy metals on biofilm-coated microplastics and their implication for the progression of neurodegenerative diseases.

Microplastic (MP) tiny fragments (< 5 mm) of conventional and specialized industrial polymers are persistent and ubiquitous in both aquatic and terrestrial ecosystem. Breathing, ingestion, consumption of food stuffs, potable water, and skin are possible routes of MP exposure that pose potential human health risk. Various microorganisms including bacteria, cyanobacteria, and microalgae rapidly colonized on MP surfaces which initiate biofilm formation. It gradually changed the MP surface chemistry and polymer properties that attract environmental metals. Physicochemical and environmental parameters like polymer type, dissolved organic matter (DOM), pH, salinity, ion concentrations, and microbial community compositions regulate metal adsorption on MP biofilm surface. A set of highly conserved proteins tightly regulates metal uptake, subcellular distribution, storage, and transport to maintain cellular homeostasis. Exposure of metal-MP biofilm can disrupt that cellular homeostasis to induce toxicities. Imbalances in metal concentrations therefore led to neuronal network dysfunction, ROS, mitochondrial damage in diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Prion disorder. This review focuses on the biofilm development on MP surfaces, factors controlling the growth of MP biofilm which triggered metal accumulation to induce neurotoxicological consequences in human body and stategies to reestablish the homeostasis. Thus, the present study gives a new approach on the health risks of heavy metals associated with MP biofilm in which biofilms trigger metal accumulation and MPs serve as a vector for those accumulated metals causing metal dysbiosis in human body.

Dual roles of UPRer and UPRmt in neurodegenerative diseases.

The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic reticulum and mitochondria, a dynamic balance exists between protein folding mechanisms and unfolded protein levels under normal conditions. Disruption of this balance or an accumulation of unfolded proteins in these organelles can result in stress responses and UPR. The UPR restores organelle homeostasis and promotes cell survival by increasing the expression of chaperone proteins, regulating protein quality control systems, and enhancing the protein degradation pathway. However, prolonged or abnormal UPR can also have negative effects, including cell death. Therefore, many diseases, especially neurodegenerative diseases, are associated with UPR dysfunction. Neurodegenerative diseases are characterized by misfolded proteins accumulating and aggregating, and neuronal cells are particularly sensitive to misfolded proteins and are prone to degeneration. Many studies have shown that the UPR plays an important role in the pathogenesis of neurodegenerative diseases. Here, we will discuss the possible contributions of the endoplasmic reticulum unfolded protein response (UPRer) and the mitochondrial unfolded protein response (UPRmt) in the development of several neurodegenerative diseases.

The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.

La neurodegeneración desde un punto de vista holístico / A holistic insight into neurodegeneration

Las enfermedades neurodegenerativas se caracterizan por un deterioro neuronal progresivo e irreversible. Aunque constituyen un grupo de patologías muy heterogéneo, la mayoría comparten un origen multifactorial y una estrecha relación con el envejecimiento. El aumento de la esperanza de vida a nivel mundial ha convertido a estas patologías en una amenaza para los sistemas sanitarios y de cuidados, pues su prevalencia crece de forma paralela al envejecimiento de la población. Destacan entre ellas, por su elevada prevalencia o por el impacto sanitario que tienen, las enfermedades de Alzheimer, Parkinson y Huntington; y la esclerosis lateral amiotrófica. El conocimiento sobre el origen de estas enfermedades es generalmente muy limitado, lo que condiciona la extrema dificultad de su manejo clínico. No existen métodos fiables para su diagnóstico temprano, por lo que su detección se suele producir cuando el deterioro clínico es ya irreversible. Por otra parte, los tratamientos disponibles hoy en día son meramente paliativos, ya que el desconocimiento sobre las causas primarias de la enfermedad y su diagnóstico tardío impiden el desarrollo de tratamientos capaces de detener o revertir el deterioro estructural y funcional. En los últimos años se han identificado varios fenómenos patológicos que podrían constituir las verdaderas causas primigenias de estas enfermedades, destacando el estrés oxidativo, las alteraciones de la proteostasis y la neuroinflamación: en las conexiones entre ellos y en su capacidad para retroalimentarse podrían estar algunas de las respuestas necesarias para avanzar hacia un abordaje clínico efectivo de los procesos neurodegenerativos.(AU)

Neurodegenerative diseases are defined by a progressive and irreversible impairment of neurons. Despite being a very heterogeneous group of pathologies, they share some common features, such as their multifactorial origin and their close correlation with ageing. As worldwide life expectancy increases, these diseases have become a tough challenge for healthcare systems as their prevalence is raising in the same way. The most important neurodegenerative disorders, because of their prevalence or their health impact, are Alzheimer´s, Parkinson´s and Huntington´s diseases; and amyotrophic lateral sclerosis. The knowledge about their origin is still very poor, so their clinical management is far from being adequate. There are not reliable methods for early diagnosis, so these diseases are usually detected when tissue damage is irreparable. Furthermore, current available therapies are intended only for symptomatic relief, since the misunderstanding about the real causes of these diseases and their delayed diagnosis hinder the development of new treatments being able to stop or even reverse the structural and functional decline. In the last few years, some pathological events have been identified as potential key factors to understand the origin of neurodegeneration. Among them, we shall mention oxidative stress, impaired proteostasis and neuroinflammation: a deeper knowledge about their interconnections and their ability to feedback each other could provide valuable information to progress towards an effective clinical management of neurodegenerative disorders.(AU)

Exercise for prevention of falls and fall-related injuries in neurodegenerative diseases and aging-related risk conditions: a meta-analysis.

Introduction: Neurodegenerative diseases often cause motor and cognitive deterioration that leads to postural instability and motor impairment, while aging-associated frailty frequently results in reduced muscle mass, balance, and mobility. These conditions increase the risk of falls and injuries in these populations. This study aimed to determine the effects of exercise on falls and consequent injuries among individuals with neurodegenerative diseases and frail aging people. Methods: Electronic database searches were conducted in PubMed, Cochrane Library, SportDiscus, and Web of Science up to 1 January 2023. Randomized controlled trials that reported the effects of exercise on falls and fall-related injuries in neurodegenerative disease and frail aging people were eligible for inclusion. The intervention effects for falls, fractures, and injuries were evaluated by calculating the rate ratio (RaR) or risk ratio (RR) with 95% confidence interval (CI). Results: Sixty-four studies with 13,241 participants met the inclusion criteria. Exercise is effective in reducing falls for frail aging people (RaR, 0.75; 95% CI, 0.68-0.82) and participants with ND (0.53, 0.43-0.65) [dementia (0.64, 0.51-0.82), Parkinson's disease (0.49, 0.39-0.69), and stroke survivors (0.40, 0.27-0.57)]. Exercise also reduced fall-related injuries in ND patients (RR, 0.66; 95% CI, 0.48-0.90) and decreased fractures (0.63, 0.41-0.95) and fall-related injuries (0.89, 0.84-0.95) among frail aging people. For fall prevention, balance and combined exercise protocols are both effective, and either short-, moderate-, or long-term intervention duration is beneficial. More importantly, exercise only induced a very low injury rate per participant year (0.007%; 95% CI, 0-0.016) and show relatively good compliance with exercise (74.8; 95% CI, 69.7%-79.9%). Discussion: Exercise is effective in reducing neurodegenerative disease- and aging-associated falls and consequent injuries, suggesting that exercise is an effective and feasible strategy for the prevention of falls.

The Effects of Long-term, Low-dose ß-N-methylamino-L-alanine (BMAA) Exposures in Adult SODG93R Transgenic Zebrafish.

ß-N-Methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by cyanobacteria, which has been implicated in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). It is postulated that chronic exposure to BMAA can lead to formation of protein aggregates, oxidative stress, and/or excitotoxicity, which are mechanisms involved in the etiology of ALS. While specific genetic mutations are identified in some instances of ALS, it is likely that a combination of genetic and environmental factors, such as exposure to the neurotoxin BMAA, contributes to disease. We used a transgenic zebrafish with an ALS-associated mutation, compared with wild-type fish to explore the potential neurotoxic effects of BMAA through chronic long-term exposures. While our results revealed low concentrations of BMAA in the brains of exposed fish, we found no evidence of decreased swim performance or behavioral differences that might be reflective of neurodegenerative disease. Further research is needed to determine if chronic BMAA exposure in adult zebrafish is a suitable model to study neurodegenerative disease initiation and/or progression.

New-onset neurodegenerative diseases as long-term sequelae of SARS-CoV-2 infection: A systematic review and meta-analysis.

The association between SARS-CoV-2 infection with increased risk for new-onset neurodegenerative diseases remains unclear. Therefore, this meta-analysis aims to elucidate whether new-onset neurodegenerative diseases are long-term sequelae of SARS-CoV-2 infection. PubMed/MEDLINE, CENTRAL, and EMBASE were systematically searched for articles published up to January 10, 2023. A systematic review and meta-analysis were performed to calculate the pooled effect size, expressed as hazard ratios (HR) with corresponding 95% confidence interval (CI) of each outcome. Twelve studies involving 33 146 809 individuals (2 688 417 post-COVID-19 cases and 30 458 392 controls) were included in the present meta-analysis. The pooled analyses compared with control groups showed a significant association between SARS-CoV-2 infection and increased risk for new-onset Alzheimer's disease (HR = 1.50, 95% CI 1.22-1.85, I2 = 97%), dementia (HR = 1.66, 95% CI 1.42-1.94, I2 = 91%), and Parkinson's disease (HR = 1.44, 95% CI 1.06-1.95, I2 = 86%) among COVID-19 survivors. SARS-CoV-2 infection may be associated with a higher risk for new-onset neurodegenerative diseases in recovered COVID-19 patients. Future studies are warranted to determine the biological mechanisms underlying the neurodegenerative consequences of COVID-19 as long-term sequelae of SARS-CoV-2 infection.

The Role of Hydrogen Sulfide in Regulation of Cell Death following Neurotrauma and Related Neurodegenerative and Psychiatric Diseases.

Injuries of the central (CNS) and peripheral nervous system (PNS) are a serious problem of the modern healthcare system. The situation is complicated by the lack of clinically effective neuroprotective drugs that can protect damaged neurons and glial cells from death. In addition, people who have undergone neurotrauma often develop mental disorders and neurodegenerative diseases that worsen the quality of life up to severe disability and death. Hydrogen sulfide (H2S) is a gaseous signaling molecule that performs various cellular functions in normal and pathological conditions. However, the role of H2S in neurotrauma and mental disorders remains unexplored and sometimes controversial. In this large-scale review study, we examined the various biological effects of H2S associated with survival and cell death in trauma to the brain, spinal cord, and PNS, and the signaling mechanisms underlying the pathogenesis of mental illnesses, such as cognitive impairment, encephalopathy, depression and anxiety disorders, epilepsy and chronic pain. We also studied the role of H2S in the pathogenesis of neurodegenerative diseases: Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, we reviewed the current state of the art study of H2S donors as neuroprotectors and the possibility of their therapeutic uses in medicine. Our study showed that H2S has great neuroprotective potential. H2S reduces oxidative stress, lipid peroxidation, and neuroinflammation; inhibits processes associated with apoptosis, autophagy, ferroptosis and pyroptosis; prevents the destruction of the blood-brain barrier; increases the expression of neurotrophic factors; and models the activity of Ca2+ channels in neurotrauma. In addition, H2S activates neuroprotective signaling pathways in psychiatric and neurodegenerative diseases. However, high levels of H2S can cause cytotoxic effects. Thus, the development of H2S-associated neuroprotectors seems to be especially relevant. However, so far, all H2S modulators are at the stage of preclinical trials. Nevertheless, many of them show a high neuroprotective effect in various animal models of neurotrauma and related disorders. Despite the fact that our review is very extensive and detailed, it is well structured right down to the conclusions, which will allow researchers to quickly find the proper information they are interested in.

TBCK syndrome: a rare multi-organ neurodegenerative disease.

TBCK syndrome is an autosomal recessive disorder primarily characterized by global developmental delay, hypotonia, abnormal magnetic resonance imaging (MRI), and distinctive craniofacial phenotypes. High variability is observed among affected individuals and their corresponding variants, making clinical diagnosis challenging. Here, we discuss recent breakthroughs in clinical considerations, TBCK function, and therapeutic development.

Dietary Trace Elements and the Pathogenesis of Neurodegenerative Diseases.

Trace elements such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) are absorbed from food via the gastrointestinal tract, transported into the brain, and play central roles in normal brain functions. An excess of these trace elements often produces reactive oxygen species and damages the brain. Moreover, increasing evidence suggests that the dyshomeostasis of these metals is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, prion diseases, and Lewy body diseases. The disease-related amyloidogenic proteins can regulate metal homeostasis at the synapses, and thus loss of the protective functions of these amyloidogenic proteins causes neurodegeneration. Meanwhile, metal-induced conformational changes of the amyloidogenic proteins contribute to enhancing their neurotoxicity. Moreover, excess Zn and Cu play central roles in the pathogenesis of vascular-type senile dementia. Here, we present an overview of the intake, absorption, and transport of four essential elements (Fe, Zn, Cu, Mn) and one non-essential element (aluminum: Al) in food and their connections with the pathogenesis of neurodegenerative diseases based on metal-protein, and metal-metal cross-talk.

Emerging Symptomatic Treatment of Chronic Traumatic Encephalopathy (CTE): a narrative review.

INTRODUCTION: Chronic traumatic encephalopathy (CTE) is an emergent neurodegenerative tauopathy well characterized pathologically but with limited consensus about clinical criteria. The clinical features include cognitive, behavioral, and motor symptoms such as parkinsonism, gait, balance disorder, and bulbar impairment. Their recognition derives from retrospective studies in pathologically confirmed CTE patients. This is one of the main reasons for the lack of specific pharmacological studies targeting symptoms or pathologic pathways of this disease. AREAS COVERED: In this narrative review, we overview the possible symptomatic treatment options for CTE, based on pathological similarities with other neurodegenerative diseases that may share common pathological pathways with CTE. The PubMed database was screened for articles addressing the symptomatic treatment of CTE and Traumatic Encephalopathy Syndrome (TES). Additional references were retrieved by reference cross-check and retained if pertinent to the subject. The clinicaltrials.gov database was screened for ongoing trials on the treatment of CTE. EXPERT OPINION: The similarities with the other tauopathies allow us, in the absence of disease-specific evidence, to translate some knowledge from these neurodegenerative disorders to CTE's symptomatic treatment, but any conclusion should be drawn cautiously and a patient-tailored strategy should be always preferred balancing the risks and benefits of each treatment.

Cerebral Small Vessel Disease-Related Dementia: More Questions Than Answers.

Cerebral small vessel disease (CSVD) has emerged as a common factor driving age-dependent diseases, including stroke and dementia. CSVD-related dementia will affect a growing fraction of the aging population, requiring improved recognition, understanding, and treatments. This review describes evolving criteria and imaging biomarkers for the diagnosis of CSVD-related dementia. We describe diagnostic challenges, particularly in the context of mixed pathologies and the absence of highly effective biomarkers for CSVD-related dementia. We review evidence regarding CSVD as a risk factor for developing neurodegenerative disease and potential mechanisms by which CSVD leads to progressive brain injury. Finally, we summarize recent studies on the effects of major classes of cardiovascular medicines relevant to CSVD-related cognitive impairment. Although many key questions remain, the increased attention to CSVD has resulted in a sharper vision for what will be needed to meet the upcoming challenges imposed by this disease.

Association between animal protein sources and risk of neurodegenerative diseases: a systematic review and dose-response meta-analysis.

CONTEXT: Current findings about the differential effects of various sources of dietary animal protein on the risk of neurodegenerative diseases are contradictory. OBJECTIVE: The current meta-analysis was conducted to investigate the associations between intake of dietary animal protein sources and the risk of neurodegenerative diseases. DATA SOURCES: PubMed, Scopus, Web of Science, and Google Scholar databases were searched systematically until October 2021. DATA EXTRACTION: Prospective cohort studies exploring the association between consumption of animal protein sources and risk of neurodegenerative diseases in the general population were included. Among 10 571 identified studies, 33 prospective cohort studies met the eligibility criteria. DATA ANALYSIS: Dietary fish consumption was associated with a reduced risk of Alzheimer's disease (RR = 0.75; 95%CI, 0.57-0.97), dementia (RR = 0.84; 95%CI, 0.75-0.93), and cognitive impairment (RR = 0.85; 95%CI, 0.81-0.95). The risk of developing Parkinson's disease was significantly higher among those in the highest vs the lowest intake categories of total dairy (RR = 1.49; 95%CI, 1.06-2.10) and milk (RR = 1.40; 95%CI, 1.13-1.73). Moreover, dietary intake of total dairy (RR = 0.89; 95%CI, 0.80-0.99), total meat (RR = 0.72; 95%CI, 0.57-0.90), and poultry (RR = 0.82; 95%CI, 0.68-0.99) was significantly associated with a lower risk of cognitive impairment. A linear dose-response meta-analysis revealed that each 200-g increase in total daily dairy intake was associated with an 11% higher risk of Parkinson's disease and a 12% lower risk of cognitive impairment. Furthermore, there was a strong linear association between fish consumption and reduced risk of dementia. CONCLUSION: Dairy consumption is associated with an increased risk of Parkinson's disease, but a higher intake of fish may be associated with lower risk of neurodegenerative disease. Future well-controlled, randomized clinical trials are essential to validate the present findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021281887.

Role of TREM2 in the Development of Neurodegenerative Diseases After Traumatic Brain Injury.

Traumatic brain injury (TBI) has been found as the primary cause of morbidity and disability worldwide, which has posed a significant social and economic burden. The first stage of TBI produces brain edema, axonal damage, and hypoxia, thus having an effect on the blood-brain barrier function, promoting inflammatory responses, and increasing oxidative stress. Patients with TBI are more likely to develop post-traumatic epilepsy, behavioral issues, as well as mental illnesses. The long-term effects arising from TBI have aroused rising attention over the past few years. Microglia in the brain can express the triggering receptor expressed on myeloid cells 2 (TREM2), which is a single transmembrane receptor pertaining to the immunoglobulin superfamily. The receptor has been correlated with a number of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and other relevant diseases. In this review, it is demonstrated that TREM2 is promising to serve as a neuroprotective factor for neurodegenerative disorders following TBI by modulating the function of microglial cells. Accordingly, it has potential avenues for TREM2-related therapies to improve long-term recovery after TBI.