Alzheimer & Parkinson

The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative...

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian...

Lysophosphatidylinositol (LPI) is an endogenous GPR55 agonist, yet its role in Alzheimer's disease (AD) remains unclear. Here, we performed serum metabolomic profiling in 5xFAD mice and observed a reduction in multiple LPI species prior to the onset of overt Aβ pathology, and this decrease was further corroborated in human cohort samples. Exogenous LPI treatment reduced cerebral Aβ deposition, improved performance in learning and memory behavioral tasks, reduced pathological microglial...

Alzheimer's disease (AD) commences with the preclinical stage where individuals remain cognitively unimpaired but already have AD pathology. As fluid and neuroimaging biomarker research progresses, AD has become defined biologically rather than based on traditional clinical symptoms. While the diagnosis of AD has been conceptually advanced by the AT(N) classification framework according to core biomarker profiles of amyloid-β (A), tau (T) and neurodegeneration (N), solely relying on biological...

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer's disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic...

Cognitive flexibility declines early in Alzheimer's disease, yet the underlying circuit mechanisms remain unknown. Here, we report that young 5xFAD mice exhibit deficits in instrumental reversal learning prior to spatial memory impairment. This behavioral inflexibility is associated with abnormal neuronal reactivation in the medial prefrontal cortex and dorsomedial striatum. Electrophysiological recordings reveal that medial prefrontal cortex neurons are hyperexcitable and receive increased...

CONCLUSION: Early PD + pRBD exhibit specific and more severe neurofunctional network impairment pattern. Characterized by more significantly disrupted neurofunctional network topology and widespread functional connectivity abnormalities across multiple brain networks, with potential functional network reorganization. These functioning abnormalities may serve as imaging biomarkers for this clinically malignant subtype and provide potential neurobiological mechanism for understanding its poorer...

Bisphenol-A (BPA), a ubiquitous component of polycarbonate plastics and epoxy resins, has emerged as a significant environmental risk factor for neurodegenerative diseases, particularly Alzheimer's disease (AD). It is widely detected in the environment and humans due to its extensive use in plastics and epoxy resins for consumer products such as bottles, containers, and tableware. This review synthesizes current evidence on the molecular and cellular mechanisms by which BPA exposure may...

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and the accumulation of α-synuclein-containing Lewy bodies. Growing evidence indicates that neuroinflammation, particularly through the activation of Toll-like receptors (TLRs), contributes significantly to PD pathogenesis. TLRs, particularly TLR2 and TLR4, detect endogenous damage-associated molecular patterns such as misfolded α-synuclein. This recognition initiates signaling...

Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can...

Phase separated condensates of α-synuclein (α-Syn) accelerate amyloid fibril formation, a process implicated in Parkinson's disease pathogenesis. Yet, the precise effects of pathologically relevant α-Syn sequence modifications on this process remain unclear. Here, we show that sequence truncations exert the strongest influence on condensate thermodynamics, material properties, and amyloid aggregation, whereas familial point mutations impart minimal effects. Among the tested familial variants...

Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of...

Neurofeedback, which consists of recording and visualizing neural activity in real-time, is a method currently being investigated as a supplementary treatment for Parkinson's disease (PD). By using implanted deep brain stimulation (DBS) electrodes with interleaved sensing capability, previous studies have demonstrated the efficacy of neurofeedback based on beta oscillations in the basal ganglia. Herein, for the first time, we explored short-term neurofeedback ability over the course of multiple...

Rho-associated protein kinase (ROCK) is a serine/threonine kinase that plays a central role in regulating cellular processes, including growth, proliferation, survival, and migration. ROCK exists as two isoforms, ROCK1 and ROCK2, which function as the principal downstream effectors of Rho GTPases. Activation of the RhoA-ROCK signaling pathway is induced by a variety of extracellular stimuli, including angiotensin II (Ang II), platelet-derived growth factor (PDGF), integrins, and vascular...

CONCLUSIONS: Pharmacotherapies targeting neurotransmitters, the gut-brain axis, and inflammatory pathways may offer comparatively favorable cognitive benefits in AD. However, variations in safety profiles across intervention classes highlight the need for careful benefit-risk assessment. Given the limited evidence base for certain strategies, further high-quality RCTs are warranted to confirm these findings.

Metabolic alterations are increasingly implicated in neurological disorders, including Alzheimer's disease (AD), highlighting the relevance of the peripheral metabolome, shaped by genetic and environmental exposures, for brain health. We examined the relation of 991 blood metabolites with cognition and magnetic resonance imaging (MRI) measures cross-sectionally in 1,082 dementia-free middle-aged participants of the population-based Rotterdam Study and quantified contributions of genetic...

Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, is a central epigenetic regulator that links histone acetylation-dependent chromatin remodelling to transcriptional control. Through recognition of acetylated lysine residues and recruitment of transcriptional machinery, it is increasingly recognised as a critical regulator of neuronal and glial functions, influencing synaptic plasticity, neuroinflammation, learning, memory, and behavioural...

Necroptosis is a form of controlled cell death implicated in neuronal loss observed in neurodegenerative diseases such as Alzheimer's disease. Down syndrome (DS) is also characterized by the presence of neuronal cell loss, but the underlying mechanisms remain unclear. Brain tissue from a mouse model of DS, Ts65dn mice, and subjects with DS were assessed for levels of necroptosis markers including receptor-interactive protein kinase 1 and 3, necroptosis executor mixed lineage kinase domain-like...

Antibodies are proteins prized for their ability to bind to extracellular antigens with exceptionally high affinities and specificities. These features have motivated researchers to utilize antibody-antigen binding to inhibit intracellular disease targets in the proteome, yet delivery of antibodies into the cytosol of cells has long been a considerable challenge. Here, we outline the development of a lipid nanoparticle (LNP) platform for delivering antibodies into cells to selectively inhibit...

Studying the genetic basis of human phenotypes involves two primary strategies. Model-system experiments generate interpretable gene networks but do not establish relevance to human disease. In contrast, statistical genetics identifies variant- and gene-level associations but cannot test mechanistic models. Here, we bridge these approaches by introducing NERINE, a hierarchical model-based rare variant association test that incorporates gene network topology while remaining robust to network...