Alzheimer & Parkinson

Social isolation and loneliness are increasingly recognized as detrimental risk factors for brain health. Here, utilizing data from 383,421 participants in the UK Biobank, we identify significant associations between social isolation, loneliness, and the incidence of 11 neurological and psychiatric disorders, including major depressive disorder (MDD), schizophrenia, bipolar disorder, anxiety disorders, sleep disorders, dementia, Alzheimer's disease, Parkinson's disease, stroke, multiple...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β plaques and tau tangles. However, growing evidence indicates that deeper disruptions in cellular homeostasis contribute to disease onset and progression. Among these, impaired communication between mitochondria and the nucleus has emerged as a central yet underrecognized pathological feature. Mitochondrial-nuclear (mito-nuclear) crosstalk regulates energy metabolism, stress responses, and...

There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and...

Aging is driven in part by progressive deterioration of proteostasis and antioxidant defense, leading to cellular dysfunction and age-associated disease. The naturally occurring methylated inositol D-pinitol (DP) was reported to present metabolic, antioxidant, and anti-inflammatory effects, as well as to extend the lifespan of D. melanogaster and C. elegans through the insulin/IGF-1 signaling pathway. But the mechanism of DP on delay aging remains poorly understand. Here, we showed that 200 μM...

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Aberrant activation of the classical complement pathway in the brain is implicated in contributing to synapse loss and neurodegeneration in various neurodegenerative conditions. Given that C3aR is a druggable target in the complement pathway, we evaluated the potential of C3aR knockout (KO) to rescue neurodegeneration in a tauopathy model and neuroinflammatory responses in an acute endotoxemia model. We found that C3aR KO did not rescue Tau pathology, microglia activation markers,...

The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain an open question. Although rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus both under healthy conditions and in Alzheimer's disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged...

While exercise is shown to reduce hippocampal atrophy, the underlying molecular mechanisms remain to be fully elucidated. Animal studies suggest the myokine irisin underlies exercise-related hippocampal benefits, though human evidence is lacking. We cross-sectionally examined 74 healthy older adults (age 65.47 ± 8.56 years). Participants completed Godin Leisure-Time exercise questionnaires, provided fasting blood for irisin measurement and underwent structural MRI with hippocampal subfield...

Wearing-off (WO) is a common motor complication in Parkinson's disease (PD), characterized by the re-emergence of symptoms before the next dose of dopaminergic medication and still lacking objective, bedside-available neurophysiological biomarkers. In this study, we investigated cortical functional network alterations associated with WO using resting-state functional near-infrared spectroscopy (fNIRS), graph-theoretical analysis, and machine learning. Resting-state fNIRS signals were acquired...

Age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and related dementias, are increasingly understood as multifactorial proteinopathies involving co-aggregation of amyloidogenic proteins such as microtubule-associated protein-Tubulin-associated unit protein (Tau), α-synuclein (α-syn), amyloid-β (Aβ), and TAR DNA-binding protein 43 (TDP-43). Rather than acting independently, these proteins often cross-seed, co-localize, and modulate each other's...

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Aberrant activation of innate immune signaling is known to contribute to neuroinflammation in age-related neurological disorders, but the mechanisms underlying this activation remain unclear. Here, we discovered that protein S-nitrosylation, a redox-based posttranslational modification, regulates the stimulator of interferon genes (STING) protein in Alzheimer's disease (AD). Using a combination of redox chemical biology and mass spectrometry, we identified S-nitrosylation at cysteine 148 as a...

Nanoscopic aggregates of alpha-synuclein (ɑSyn) have been observed in Parkinson's disease (PD). However, the processes that occur in vivo leading to the formation of these small aggregates are not well understood. We used ultra-sensitive single-molecule methods, including single molecule array (SIMOA), and super-resolution microscopy to quantify and characterize ɑSyn aggregates harvested from human brain samples, alongside a mouse model of synucleinopathy, using different tissue processing...

Dysfunctional autophagy, a key cellular cleaning process, is a key driver of brain ageing and neurodegenerative diseases such as Alzheimer's disease (AD). However, developing effective treatments by enhancing autophagy has been challenging, as most known compounds act through the broad mTOR pathway, risking side effects, and few can effectively penetrate the brain. To address this, we developed DeepDrugDiscovery-a mechanism-aware, AI-powered screening platform incorporating ADMET and blood-brain...

The presence of neuromelanin is a characteristic feature of the human substantia nigra (SN); however, the mechanism of its synthesis and its role in the development of Parkinson's disease remain unclear. Here, we report that the host defense enzyme lactoperoxidase (LPO), which possesses broad antimicrobial activity on mucosal surfaces, is selectively expressed in human dopaminergic neurons, a feature not shared by the rodent SN. We also demonstrate that LPO can catalyze multiple steps of melanin...

The traditional pathological framework of Alzheimer's disease (AD) primarily focuses on the accumulation of β-amyloid (Aβ) and tau proteins. However, therapeutic strategies targeting these molecules have repeatedly encountered setbacks in clinical translation. Recent studies have progressively revealed that the dynamic interaction network among intracellular organelles plays a central role in the pathogenesis of AD. This systematic review examines the independent dysfunctions of three key...

The aberrant aggregation of tau leads to loss of its physiological functions and gain of toxic functions, and plays a crucial role in the pathogenesis of tauopathies including Alzheimer's disease (AD). Targeting tau aggregation is considered a promising strategy for treating tauopathies. The BRICHOS family consists of a variety of proteins containing the BRICHOS domain. Certain endogenous BRICHOS domains may inhibit the pathological aggregation of disease-associated proteins. However, the...

Amyloid beta (Aβ) plaque deposition in the central nervous system (CNS) is a hallmark of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), triggering robust innate immune responses. However, the role of the adaptive immune system remains less well understood. Here we show the immune microenvironment dynamics in APP23 transgenic (APP23-tg) mice modelling CNS amyloid pathology, using single-cell transcriptomics. We observed a marked increase in T-cell populations during late disease...

The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical...

An in vivo approach combining high-throughput screening with cell type-specific readouts could enable elucidation of genotype-phenotype relationships in complex tissues. We developed an in vivo gain-of-function Perturb-seq platform, termed iGOF-Perturb-seq, to build a functional atlas of ~1000 transcription factors (TFs) in astrocytes, a cell type essential to many brain functions. We then identified cofunctional modules, annotated uncharacterized TFs, and predicted disease-associated TF...