Aim: The longitudinal relationships among domain-specific subjective cognitive decline (SCD), declines in objective cognitive domains (OCD), plasma Alzheimer’s disease (AD) biomarkers, and incidence of cognitive impairment remain unclear. Methods: We studied 2,326 cognitively unimpaired adults (aged ≥ 60 years) from the Hubei Memory and Aging Cohort. SCD and objective cognition were assessed at baseline and follow-up. Changes were calculated using reliable change indices. Mild cognitive impairment (MCI) and dementia were clinically diagnosed. Baseline plasma biomarkers [Aβ42, Aβ40, p-tau181, p-tau217, (neurofilament light chain) NfL, (glial fibrillary acidic protein) GFAP] were measured using the Quanterix Simoa® platform. Results: Longitudinal changes in domain-specific SCD (memory, language, execution, and attention) over 2.05 ± 1.26 years were associated with outcomes, including declines in global and subdomain objective cognition, and incident MCI and dementia. Specifically, follow-up SCD memory correlated with a decline in objective memory (β = -0.06, P = 0.025). SCD language, attention, and execution predicted increased MCI/dementia risk. Higher global SCD was associated with lower baseline Aβ42 (β = -0.10, P = 0.049) and Aβ40 (β = -0.13, P = 0.029). Conclusion: Persistent domain-specific SCD progression is associated with greater cognitive decline and clinical impairment in cognitively unimpaired older adults, and correlates with plasma Aβ levels.
Sporadic Parkinson’s disease (PD) is increasingly viewed as a multifactorial neurodegenerative syndrome driven by complex interactions between genetic predisposition, environmental exposures, aging-related vulnerability, and systemic dysfunctions beyond the central nervous system. Far from just a localized dopaminergic deficit, PD pathology encompasses the sensory–gut–midbrain axis and incorporates metabolic, immune, and peripheral nervous system abnormalities. This review summarizes recent advances in four dimensions. First, we highlight key genetic contributors, such as SNCA, NEAT1, and ATP13A2/PARK9, alongside environmental stressors and aging-related changes that collectively influence disease susceptibility. Second, using cross-species transcriptomic data from humans and mice, we pinpoint conserved gene networks shared across the midbrain, gut, and sensory systems. These networks include genes (PINK1, PRKN1, LRRK2, PARK7/DJ-1, SCN9A, FAAH and GCH1) involved in key pathways regulating mitochondrial quality control and oxidative stress, autophagy-mediated protein clearance, neural development and synaptic signaling, and immune-metabolic regulation, providing molecular evidence that PD manifests as a systemic network disorder. Third, we examine current and emerging therapeutic strategies, emphasizing the move from symptom relief to disease-modifying interventions through systemic, network-level, and precision approaches. Finally, we address the expanding role of early diagnostic biomarkers and computational subtyping in enabling precision-guided therapy. These insights point to future PD care relying on multidimensional strategies - combining targets co-expressed in central and peripheral neural systems, systemic regulatory modulation, and individualized care - to slow progression and ultimately prevent disease onset. This systemic and integrative perspective could shed new light on clinical and research paradigms for PD over the coming decade.
There is a complex and potentially bidirectional association between Parkinson’s disease (PD) and periodontitis. Epidemiological studies consistently show that periodontal disease and other oral-health problems are more common in patients with PD, whereas the hypothesis that periodontitis increases PD susceptibility remains biologically plausible but not yet conclusively established. Mechanistically, PD-related motor and non-motor symptoms can impair oral self-care and worsen periodontal status; conversely, chronic periodontal infection may contribute to neurodegenerative stress through oral dysbiosis, the oral-gut-brain axis, microglial activation, Th1-skewed immune responses, oxidative stress, ferroptosis-related injury, and pathogen-associated effects on α-synuclein biology. Importantly, part of the observed association may also reflect shared modifiers, particularly vitamin D status and diet, which may influence both periodontal inflammation and PD-related vulnerability. Further clarification of these pathways may support more integrated oral-health management within comprehensive PD care.
Against the backdrop of global population aging, prostate cancer (PCa), as one of the most common malignant tumors in elderly men, has an association with cognitive frailty (CF) that has garnered increasing attention. CF significantly elevates the risk of adverse health outcomes such as dementia, falls, disability, and mortality in elderly PCa patients. This review systematically summarizes the existing evidence regarding assessment tools, underlying mechanisms, and intervention strategies for CF in elderly PCa patients. Currently, there is no gold standard for PCa-specific CF assessment. The pathogenesis of CF involves complex interactions among multiple pathways: age-related physiological decline, chronic systemic inflammation induced by PCa and its treatments, neuroendocrine dysregulation, oxidative stress, blood-brain barrier impairment, and psychosocial factors. Interventions for CF encompass non-pharmacological strategies and emerging pharmacological treatments. However, these approaches face challenges, including undefined optimal protocols, poor long-term adherence, and insufficient clinical validation. Future research should focus on: developing and validating integrated CF assessment tools tailored for PCa patients; elucidating the molecular mechanisms of CF in the context of PCa; designing and validating personalized, multimodal intervention regimens; bridging the digital divide to advance clinical translation of digital health technologies; rigorously evaluating the benefit-risk profiles of pharmacological interventions through large-scale, long-term clinical trials. Addressing CF in elderly PCa patients is crucial for optimizing disease management, improving quality of life, and guiding targeted clinical interventions.
Since the first report of Alzheimer’s disease (AD) in 1906, scientists have made remarkable progress in elucidating its molecular mechanisms, pathogenic processes, and core neuropathological features. However, effective therapeutic strategies for AD remain elusive, and the disease is still fundamentally incurable. The use of animal models constitutes a critical step in investigating pathological mechanisms and conducting preclinical experiments. With advances in transgenic technology, a variety of mouse models have been developed to replicate the pathological changes, as well as cognitive and motor impairments, observed in AD patients. These models have played a pivotal role in studying the pathogenesis of AD and screening potential therapeutic approaches. For example, the Tg2576 mouse model can simulate AD-related pathological alterations, including β-amyloid (Aβ) plaque deposition, neuroinflammation, and cognitive impairment. Nevertheless, mouse models have limitations in mimicking the complex pathology and clinical manifestations of human AD. In contrast, some medium- to large-sized animals in nature, such as canines and non-human primates (NHPs), can spontaneously develop AD-like pathological changes. For instance, NHPs exhibit high similarity to humans in terms of brain structure and function, and their spontaneous AD-like pathological changes provide a more human-relevant model for investigating AD pathogenesis and drug screening. This article elaborates on the pathological characteristics, clinical manifestations, advantages, and disadvantages of five distinct animal models (mouse, cat, dog, sheep and NHPs) in experimental research, thereby providing a reference for model selection in AD studies.
α-Synuclein (α-syn) aggregation represents a key pathological hallmark of Parkinson’s disease (PD), with its aggregation and propagation closely associated with disease progression. While the precise mechanisms underlying α-syn amyloidogenesis remain unclear, iron deposition, another prominent pathological feature in PD, has been shown to promote α-syn aggregation through undefined pathways. Conversely, α-syn aggregates may influence iron-dependent cell death pathways. In this mini-review, we synthesize recent evidence on the direct structural interactions between iron and α-syn, the iron-mediated regulation of α-syn protein turnover, and the potential mechanisms by which α-syn promotes iron-dependent cell death. By elucidating these bidirectional interactions between proteinopathy and redox imbalance, we aim to provide mechanistic insights for developing pathology-targeted therapeutic strategies in PD.
Patent foramen ovale (PFO) is prevalent in approximately 25% of the general population and the incidence reaches up to 50% among patients with cryptogenic stroke (CS). Extensive research indicates that PFO is linked to paradoxical embolism, leading to CS, embolic stroke of undetermined source, and systemic embolization. Percutaneous PFO closure (PPFOC) has been a promising approach to prevent recurrent ischemic stroke, particularly in selected CS patients under 60 years with a high-risk PFO. Despite advancements, unresolved issues persist. In this review, we provide an updated overview of the diagnosis of high-risk PFOs and summarize recent insights into whether closure or medical therapy alone is effective for reducing recurrent ischemic stroke in CS patients with PFOs. Additionally, we present the current evidence about the safety and effectiveness of PFO percutaneous closure in elderly CS patients. Lastly, we discuss the incidence and the management of atrial fibrillation after PFO closure to guide clinicians in their decision making. Emphasizing the importance of comprehensive assessment, we advocate for a close multidisciplinary collaboration, including neurologists and cardiologists, to avoid unnecessary closure and associated complications in CS patients with a PFO.
The abnormal deposition of pathological proteins in Alzheimer’s disease (AD) can disrupt neural pathways in the brain. Functional magnetic resonance imaging (fMRI) is a valuable tool for detecting changes in brain connectivity caused by AD, offering significant support for early diagnosis. However, traditional numerical distribution methods often struggle to capture subtle lesions in fMRI images, limiting their diagnostic utility. The study discussed in this commentary introduces a spatiotemporal graph convolutional network (ST-GCN) framework that integrates both spatial and temporal dependencies in brain functional networks, providing a more robust approach to fMRI data analysis. This advancement significantly improves the identification of functional connectivity (FC) biomarkers for AD. This commentary critically evaluates the strengths and limitations of the proposed approach and outlines potential future research directions, particularly in the integration of multimodal neuroimaging data and further validation of the model across diverse clinical populations.
α-synucleinopathy, as represented by Parkinson’s disease and dementia with Lewy bodies, is a group of common neurodegenerative diseases that have insidious onset and irreversible progression. Therefore, identifying markers related to neurodegenerative progression during the prodromal stage is crucial for the early diagnosis and effective treatment of α-synucleinopathy. A distinct parasomnia, isolated rapid eye movement sleep behavior disorder (iRBD), is confirmed as the most specific prodromal phase of α-synucleinopathy, with most of the patients with iRBD eventually converting into a subtype of α-synucleinopathy. Throughout the disease progression of α-synucleinopathy, an array of multidimensional markers, such as clinical, neuroimaging, and neuropathological markers, have been increasingly discovered and validated. These markers may hold potential diagnostic, disease-monitoring, and prognostic values for iRBD. In this review, we summarized the current evidence on the neurodegenerative markers associated with iRBD and discussed their significant role in the diagnosis, monitoring, and prediction of phenoconversion into α-synucleinopathy in iRBD. A better understanding of these markers will facilitate their implementation in risk stratification, population selection for future clinical trials, and monitoring of response to the disease-modifying strategies in iRBD.
Dementia can be broadly categorized into neurodegenerative dementias and non-neurodegenerative forms. Neurodegenerative dementias include Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), neuronal intranuclear inclusion disease (NIID), dementia with Lewy bodies (DLB), Huntington’s disease (HD), and prion diseases. Genetic factors play a central role in the etiology of neurodegenerative dementias. In AD, heritability estimates range from 58%-79% for late-onset AD (LOAD) and over 90% for early-onset AD, with causal genes including APP, PSEN1, and PSEN2. LOAD is a complex polygenic disease. Genome-wide association studies have identified more than 70 susceptibility loci, among which APOE ε4 is the most established genetic risk factor; carriers of the APOE ε4/ε4 genotype are now considered genetically predisposed to AD. However, the known heritability of AD remains incomplete, with rare variants in dozens of genes contributing substantially to disease risk. FTLD often presents with behavioral and language impairments, with MAPT, C9orf72, and GRN being the most commonly implicated causal genes. DLB, which overlaps clinically with Parkinson’s disease dementia, shares genetic risk factors with both AD and PD, including APOE, BIN1, SNCA, and GBA. NIID is caused by abnormal NOTCH2NLC GGC repeat expansions, which correlate with disease phenotype and age of onset. HD results from abnormal CAG repeat expansions in the HTT gene. Prion diseases arise from variants in the PRNP gene, with M129V being a notable risk factor. These findings underscore the pivotal role of genetic factors in the pathogenesis of neurodegenerative dementias.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) plaques, and neurofibrillary tangles. Despite extensive research, its pathogenesis remains incompletely understood and no disease-modifying therapies are currently available. While early studies focused on neuronal dysfunction, growing evidence implicates glial cells - including microglia, astrocytes, and oligodendrocytes - in driving AD pathogenesis. Microglia initially clear Aβ and cellular debris; however, chronic activation triggers the release of proinflammatory cytokines that worsen Aβ and tau pathology and induce neurotoxic astrocytes. Reactive astrocytes compromise blood-brain barrier integrity, secrete inflammatory mediators, and impair synaptic transmission. Oligodendrocytes and their progenitors, beyond their role in myelination, can adopt disease-associated states that alter metabolic support and immune signaling, yielding both protective and detrimental effects. Recent multi-omics studies have identified critical regulatory pathways, including NF-κB, the NLRP3 inflammasome, and the cGAS-STING axis, that govern glial phenotype transitions. Therapeutic strategies targeting these pathways, such as small-molecule inhibitors, immunomodulators, and NAD+ precursors, have shown promise in preclinical AD models by reducing neuroinflammation, restoring glial homeostasis, and improving cognition. In this review, we summarize glial cell functions in health and disease, dissect molecular mechanisms of glial dysfunction in AD, and evaluate emerging glia-directed therapies. Finally, we discuss translational challenges and outline future directions for leveraging glial biology in the development of effective AD therapies.
When two individuals share a common experience, their heartbeats can become synchronized in a phenomenon known as cardiac physiological synchrony (CPS). This interpersonal coupling of heart rate and heart rate variability is considered a component of social behavior and may facilitate close emotional, physical, and prosocial interactions. However, the exact mechanisms underlying CPS are unknown, including its potential differential roles in various types of empathy. Notably, CPS is distinct from the direct electrical coupling that occurs between cardiomyocytes. We therefore review the current literature on CPS and the hypothesized mechanisms driving heartbeat synchronization. The consequences of either reduced or increased CPS during social interaction are not well studied. Existing evidence suggests that CPS may tune social interaction, potentially promoting prosociality or alleviating stress and anxiety depending on context. We hypothesize that variations in CPS may correspond to different types of empathy and could be linked to specific types of anxiety. Finally, we discuss the implications of CPS for mental health, therapeutic interventions, and strategies aimed at reducing chronic stress and anxiety. A deeper understanding of CPS mechanisms and consequences could help to noninvasively improve mental and physical well-being and mitigate structural degeneration in brain regions essential for memory and cognition.
The dynamic relationship between neuronal activity and mitochondrial function plays a crucial role in cognitive health, with disruptions linked to age-related cognitive decline. In this mini review, we highlight the significant findings of Li et al., who discovered an age-dependent coupling mechanism between neuronal/synaptic excitation and excitation-dependent mitochondrial gene transcription coupling (E-TCmito). Their research revealed that enhancing brain E-TCmito in aged animals effectively mitigated age-related cognitive decline.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized by progressive motor and non-motor manifestations. Its rising prevalence poses significant challenges for clinical management and public health. Type 2 diabetes mellitus (T2DM), the most frequent metabolic disorder, shares several pathogenic mechanisms with PD, including mitochondrial dysfunction, insulin resistance, and oxidative stress. Epidemiological studies suggest a higher incidence of PD among individuals with T2DM, with growing evidence that diabetes may accelerate the onset and progression of motor and cognitive symptoms. This narrative review summarizes current knowledge on the relationship between T2DM and PD, with emphasis on epidemiological associations, shared biological pathways, and the therapeutic implications of antidiabetic agents. Available data indicate that patients with both PD and T2DM tend to experience a faster progression of motor and cognitive decline. Clinical trials assessing hypoglycemic agents have reported heterogeneous findings: pioglitazone failed to demonstrate neuroprotective effects, while exenatide showed temporary improvements in motor function that were not sustained after treatment discontinuation. Experimental studies also suggest possible neuroprotective actions of metformin and dipeptidyl peptidase 4 inhibitors, although well-designed clinical trials are still lacking. The interaction between T2DM and PD highlights the importance of metabolic factors in neurodegeneration. Further studies are required to determine the impact of diabetes and its treatments on the PD course and to explore antidiabetic drugs as potential disease-modifying therapies.
Aim:Define the subtype-specific contributions of nigrostriatal dopaminergic neurons (DANs) to motor and non-motor behaviors by comparing Calbindin 1-positive (Calb1 +) and Aldehyde dehydrogenase 1a1-positive (Aldh1a1 +) DANs. Methods:Intersectional genetic strategy and chemogenetic inhibition were applied to selectively silence Calb1 + or Aldh1a1 + DANs in mice. An adeno-associated viral vector (AAV-CreOn-FlpOn-hM4Di-P2A-mCherry) was stereotactically delivered into the substantia nigra pars compacta of double knock-in lines Th Flp; Calb1 IRESCre or Th Flp; Aldh1a1 CreERT2. Following expression, subtype-specific neuronal inhibition was induced with a designer receptor exclusively activated by designer drugs (DREADD) ligand, and the mice were assessed in assays of voluntary movement, motor skill learning, and early associative learning behavior. Results:Chemogenetic inhibition of either Calb1 + or Aldh1a1 + DANs produced a marked reduction in voluntary movement and impaired acquisition of motor skills, indicating that both subtypes are necessary for normal motor function and learning. In contrast, only inhibition of Calb1 + DANs altered early associative-learning performance, revealing a dissociable, subtype-specific role for Calb1 + neurons in reinforcement-related behavior that was not observed with Aldh1a1 + neuron inhibition. Conclusion:Both Calb1 + and Aldh1a1 + nigrostriatal DANs are key regulators of movement and motor learning, with Calb1 + neurons additionally modulating reward-based associative learning. These findings highlight the functional heterogeneity of nigrostriatal DAN subtypes and identify potential therapeutic targets for addressing motor and non-motor deficits in Parkinson's disease.
Prion diseases (PrDs) are fatal neurodegenerative disorders caused by the misfolding and aggregation of pathogenic prion protein (PrPSc). Traditional diagnostic methods have limited sensitivity and specificity, often requiring confirmation in the late stages or postmortem. In recent years, protein misfolding amplification techniques, including protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC), have achieved significant breakthroughs, enabling ultrasensitive detection of PrPSc with detection limits as low as the attogram level. These methods greatly enhance diagnostic accuracy and offer the potential for early and non-invasive detection of PrDs. Their success has extended to other seeding-based neurodegenerative diseases, such as Parkinson’s disease (PD), providing a powerful tool for early diagnosis, molecular pathology research, and clinical translation. Beyond diagnosis, these techniques play a crucial role in investigating strain characteristics and pathology, as well as in screening potential drugs for PrDs. They are also applied in research of public health security, including variant Creutzfeldt-Jakob disease (vCJD) surveillance, cross-species risk assessment, and environmental contamination monitoring and optimization of decontamination strategies. With exceptional sensitivity and specificity, these techniques are revolutionizing the landscape of neurodegenerative disease detection and intervention.
Aim: The endoplasmic reticulum (ER)-localized vesicle-associated membrane protein-associated protein B (VAPB) is implicated in many cellular processes, such as ER-organelle tethering, calcium homeostasis, and unfolded protein response. The P56S missense mutation in VAPB has been associated with familial forms of motor neuron diseases such as typical amyotrophic lateral sclerosis (ALS), atypical ALS, and spinal muscular atrophy. However, it has not been determined how the VAPB P56S mutation induces the degeneration of corticospinal motor neurons (CSMNs) in ALS. Methods: Using homozygous knock-in (KI) mice expressing P56S VAPB, we investigated the mutation's pathogenic impacts and underlying mechanisms on the survival and function of CSMNs. We performed a wide variety of assays to examine the behavioral, histological, cellular, and molecular abnormalities of KI mice. Results: Compared with wild-type controls, KI mice showed the downregulated protein level of mutant VAPB, proteinase K-resistant cytoplasmic inclusions of mutant VAPB in CSMNs, abnormal hyperactivity, impaired motor coordination, neuronal loss of CSMNs, and axonal degeneration of pyramidal and corticospinal tracts. Mechanistic studies revealed that the VAPB P56S mutation rendered the mutant protein destabilized and inclusion-prone in cortical neurons, and the proteasomal degradation played a critical role in modulating mutant VAPB’s protein level and inclusion formation. In addition, the VAPB P56S mutation disrupted ER-mitochondria contacts, impaired VAPB-PTPIP51 interaction and IP3R-VDAC interaction, elevated cytosolic Ca2+, activated CaMKII, and increased CRMP2 phosphorylation. Moreover, the VAPB P56S mutation activated the IRE1-XBP1/p38 mitogen-activated protein kinase (MAPK)/ c-Jun N-terminal kinase (JNK) pathway, increased tau hyperphosphorylation, and upregulated p53 expression and phosphorylation. Conclusion: These findings demonstrate the progressive degeneration of CSMNs induced by VAPB P56S mutation and indicate the involvement of the Ca2+-CaMKII-CRMP2 and IRE1-p38 MAPK/JNK-tau/p53 pathways in the pathogenic process.
Objectives : Observational studies have suggested associations between retinal layer thinning and increased susceptibility to Alzheimer’s disease (AD), but causal inference remains inconclusive. This study aimed to investigate potential genetic causality between inner retinal layer (IRL) thickness, specifically the retinal nerve fiber layer (RNFL) and the ganglion cell inner plexiform layer (GCIPL), and AD risk. Methods : We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics for RNFL/GCIPL thickness (n = 31,434; UK Biobank) and AD status (39,106 cases vs. 401,577 controls; European Alzheimer and Dementia Biobank). Replication was performed in an independent AD cohort (35,274 cases vs. 59,163 controls). The inverse-variance weighted (IVW) method was used as the primary analytical approach. Results : No significant associations were found between retinal thickness and AD risk (RNFL: odds ratio [OR]IVW = 1.001, 95% confidence interval [CI] = 0.986-1.017, P = 0.883; GCIPL: ORIVW = 1.008, 95% CI = 0.997-1.019, P = 0.172). Reverse MR analyses also showed no causal effect of genetic liability to AD on retinal thickness (RNFL: ORIVW = 0.907, 95% CI = 0.786-1.046, P = 0.179; GCIPL: ORIVW = 1.014, 95% CI = 0.828-1.242, P = 0.890). These findings were consistent in replication analyses (RNFL: ORIVW = 1.015, 95% CI = 0.987-1.043, P = 0.305; GCIPL: ORIVW = 1.014, 95% CI = 0.991-1.037, P = 0.237). Conclusion : This MR analysis found no evidence of a causal genetic relationship between IRL thickness variations and AD. Future investigations should focus on trans-ethnic populations, longitudinal studies, and multimodal retinal phenotyping within GWAS cohorts to further clarify this relationship.
Aim: TMPRSS6, a type II transmembrane serine protease predominantly expressed in the liver, plays a crucial role in regulating systemic iron homeostasis. However, the expression and function of TMPRSS6 in the central nervous system remain poorly understood. Methods: Adeno-associated viruses (AAVs) carrying plasmids with neuron-specific promoters for TMPRSS6 knockdown were stereotactically injected into the hippocampus of 6-month-old wild-type (WT) and amyloid precursor protein (APP)/PS1 male mice. Three months later, the mice underwent a water maze test, and hippocampal tissues were collected for subsequent experiments. Results: The analysis of Alzheimer’s disease (AD) databases we describe here identified a significant increase in TMPRSS6 mRNA levels in the hippocampus of AD patients, a finding corroborated by elevated TMPRSS6 expression in the hippocampus of APP/PS1 transgenic mice, which exhibit an AD phenotype. Knockdown of TMPRSS6 in the hippocampus of these mice led to a significant enhancement in cognitive and learning abilities, accompanied by a reduction in the accumulation of APP and amyloid-beta (Aβ) plaques. Further experiments revealed that TMPRSS6 knockdown decreased iron and reactive oxygen species (ROS) levels in the hippocampus, upregulated glutathione peroxidase 4 (GPX4), downregulated acyl-CoA synthetase long-chain family member 4 (ACSL4), ameliorated mitochondrial cristae damage, and inhibited ferroptosis, which might be associated with the bone morphogenic protein/Smad signaling pathway. Conclusion: Our findings shed light on the role of TMPRSS6 in the central nervous system, which may offer valuable insights for the development of therapeutic strategies for AD or other disorders associated with brain iron accumulation.
The incidence of neurodegenerative diseases is increasing exponentially, with Alzheimer’s disease (AD) being a notorious example. AD is a progressive, aging-related, multifactorial disease, and no uniform theory exists regarding its etiology. One hypothesis implicates defects in the organism’s mechanosensing and mechanotransduction mechanisms. The deleterious effects of mechanical stress in neurodegeneration have been proven through multiple studies and observations, but the pathways linking mechanical inputs to disease progression remain unclear. It has been proposed that the nervous tissue primarily responds to mechanical stress sources through astrocytes and microglia, with the activation of Piezo1 and TRPV4 ion channels. An area of current research is examining the theory that mechanotransduction might be involved in elevated oxidative stress and dysregulated apoptotic pathways. We have summarized the current understanding of the apoptotic pathways related to AD. Our review has indicated that the relationship between the crucial mechanosensing Hippo pathway (MST1 in humans) and TRPV4 and KCNN4 is worth following up in future studies. We noted that G3BP1 and G3BP2 in FlnA-mediated mechanosensing are linked to ceramide production, along with their interaction with the stress granules - a key element for the onset of apoptosis, which are assembled, among others, in response to oxidative stress. This review sheds light on how the response to mechanical input disrupts apoptotic pathways and what the implications in AD progression and also identifies potential targets for future research focus.
