Alzheimer & Parkinson

Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the...

Network hyperexcitability is one of the hallmarks of the early stage of Alzheimer's disease (AD). In this issue of Neuron, Papanikolaou¹ and coworkers show that AD-mediated alterations start at the excitatory-inhibitory subcircuit in the deep layers of the cortex.

RET is a receptor tyrosine kinase that plays important roles in development, cancers, and Parkinson's disease. Here, we identify immunoglobulin superfamily member 10 (IGSF10) as a RET antagonist. We show that Ewing sarcoma depends on IGSF10 and that IGSF10 prevents RET-mediated activation of cdc42, a Rho family G protein and a key regulator of Ewing sarcoma growth as well as cell migration. We demonstrate that IGSF10 binds RET and GAS1, a cell surface RET inhibitor, and assembles an inhibitory...

Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide. Recent studies highlights that mitochondrial dysfunction drives alterations in microglial function, serving as a pivotal mechanism in the pathogenesis and progression of AD. Increasingly, there is evidence that mitochondrial dysfunction encompasses energy metabolism deficits, heightened oxidative stress, impaired mitochondrial dynamics, disrupted autophagy, and calcium homeostasis imbalances. These...

Midnolin (Midn) was originally discovered as a gene expressed specifically in the mouse midbrain at the embryonic developmental stage; MIDN was localized in the nucleus/nucleolus. Although the pathophysiological roles of MIDN remained largely unknown for many years after its discovery, its molecular functions and relevance to diseases have gradually become clearer. In PC12 cells, a rat neuronal model cell line, liquidity factors that are necessary for neurite outgrowth are reported to induce...

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were...

Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to...

Measuring splicing and chromatin accessibility simultaneously in frozen tissues remains challenging. Here we combined single-cell isoform RNA sequencing and assay for transposase accessible chromatin (ScISOr-ATAC) to interrogate the correlation between these modalities in single cells in human and rhesus macaque frozen cortical tissue samples. Applying a previous definition of four 'cell states' in which the transcriptome and chromatin accessibility are coupled or decoupled for each gene, we...

The present study was conducted to construct structure connectivity (SC) and functional connectivity (FC) between different hippocampal subregions and the whole brain based on structural and function Magnetic Resonance Imaging, and to explore the changes in hippocampal subregions structural and functional connectivity in the different stages of Alzheimer's Disease (AD). 117 participants (75 female, 42 male) aged 60-88 years were recruited from the Sino-Longitudinal Study on Cognitive Decline in...

Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological...

The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a...

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking, and LRRK2-activating mutations are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including protein phosphatase, Mg2^(+)/Mn2^(+) dependent 1H (PPM1H), which acts on phosphorylated Rab 8A (phosphoRab8A) and phosphoRab10. Here, we report a phosphatome-wide small interfering RNA (siRNA) screen that identified PPM1M as a...

Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimer's disease, and its accumulation exhibits a rich spatiotemporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatiotemporal process is orchestrated, namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production, or both. To address this, we develop a...

This study introduces a novel multi-channel temporal interference stimulation (M-TIS) paradigm and rigorously evaluates its capacity to non-invasively target the globus pallidus internus (GPi), a pivotal region in Parkinson's disease (PD) treatment. Employing realistic human head models derived from MRI data and sophisticated finite element modeling, we demonstrate that M-TIS achieves significantly enhanced stimulation intensity and focality within the GPi compared to conventional single-channel...

Aging-related declines in energy metabolism represent a key risk factor for the development of amyloid pathology, the earliest hallmark of Alzheimer's disease. Aging also contributes to the emergence of the second major hallmark, tau pathology, whose propagation is facilitated by pre-existing amyloid accumulation. The overlap of amyloid and tau pathologies ultimately leads to neurodegeneration and the onset of Alzheimer's disease-the most prevalent form of dementia. Recent findings underscore a...

In Parkinson's disease (PD), α-synuclein aggregation in striatal synapses is hypothesised to trigger a cascade of events leading to synaptic loss and cortical Lewy body (LB) pathology. Using multiplex immunofluorescence and confocal microscopy on 69 brains spanning Braak stages 0-6-including controls, incidental LB disease (iLBD), and PD-we show that phosphorylated (pSer129) α-synuclein is enriched in putaminal dopaminergic synapses already in early disease stages, and associates with...

Natural language processing (NLP) can expand the utility of clinical records data in dementia research. We deployed NLP algorithms to detect core features of dementia with Lewy bodies (DLB) and applied those to a large database of patients diagnosed with dementia in Alzheimer's disease (AD) or DLB. Of 14,329 patients identified, 4.3% had a diagnosis of DLB and 95.7% of dementia in AD. All core features were significantly commoner in DLB than in dementia in AD, although 18.7% of patients with...

CHI3L1/YKL-40 is an astrocyte-secreted glycoprotein recognized as a biomarker of CNS inflammation and implicated in Alzheimer's disease (AD) cognitive decline. However, its precise pathological role remains unclear. Here, we investigate CHI3L1's function and its therapeutic potential in AD using both human induced pluripotent stem cell-derived neurogenesis models and in vivo conditional AD mouse models, with astrocyte-specific CHI3L1 knockout, alongside 5XFAD mice. Our data reveal that CHI3L1...

The intensive production and use of plastics, poor biodegradability and inadequate recycling have caused excessive and alarming environmental pollution. This has led to the inevitable intake by humans, through different routes, of small plastic particles, the micro and nano-plastics (MNPs) with sizes ranging from nanometers (<1000 nm) to micrometers (from 5 mm to 1 µm). MNPs can cause harmful effects in human tissues and organs, contributing to the early onset of aging and various age-related...

Alzheimer's Disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, we demonstrate that our robust and interpretable AI-guided tool (predictive prognostic model, PPM) enhances precision in patient stratification, improving outcomes and decreasing sample size for a AD clinical trial. The AMARANTH trial of lanabecestat, a BACE1 inhibitor, was deemed futile, as treatment did not change cognitive outcomes, despite...