Alzheimer & Parkinson

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals. We identify over 1 million candidate cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes. We define large-scale...

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Emerging gene-editing technologies, such as the CRISPR system, represent a potential pathway for precision medicine targeting the genetic and molecular causes of diseases. Second-generation CRISPR technologies, including base editing, prime editing, and engineered Cas variants, have improved fidelity and offer alternative strategies for precise gene correction, transcriptional repression or activation, and modulation of pathological pathways in neurodegeneration. These tools can correct...

Personality changes are a clinical criterion for dementia diagnosis, yet their progression across disease stages remains unclear. This systematic review and meta-analyses examined change in the five major personality traits across the preclinical, transitional, and clinical dementia stages. We conducted pre-registered searches of three databases from their inception to November 2024. The standardized mean difference (SMD) with 95% CIs were combined in random-effects meta-analyses. Prospective...

Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles. Recent evidence implicates extracellular matrix (ECM) dysfunction in disease pathogenesis, including extensive loss of perineuronal nets (PNNs). PNNs are neuron-ensheathing condensed ECM structures composed of chondroitin sulfate proteoglycans, including the main constituent aggrecan (ACAN). To explore the role of PNNs in AD, we utilize the 5xFAD model and genetically target Acan...

CONCLUSIONS: DBS significantly improved motor, neuropsychological, and quality-of-life outcomes across all PD durations, with the most substantial benefits observed in mid-duration (5-10 years) patients. While levodopa response was a consistent positive prognostic factor for motor response, caution is warranted for short-duration patients with rapidly progressive motor symptoms, as they exhibited less favorable outcomes.

Microglia are crucial targets for therapeutic interventions in diseases like Alzheimer's and stroke, but efficient gene delivery to these immune cells is challenging. We developed an adeno-associated virus (AAV) vector that achieves specific and efficient gene delivery to microglia. This vector incorporates the mIba1 promoter, GFP, miRNA target sequences (miR.Ts), WPRE, and poly(A) signal. Positioning miR.Ts on both sides of WPRE significantly suppressed non-microglial expression, achieving over...

A DNA editing tool TaqTth-hpRNA was developed in this study, composed of a compact recombinant TaqTth nuclease (832 aa) and a simple hairpin-RNA guiding probe (hpRNA). In vitro biochemical studies showed the TaqTth-hpRNA efficiently cleaves artificially synthesized single-stranded DNA without stringent sequence motif like protospacer adjacent motif (PAM). It can also cleave the genomic DNA of Escherichia coli with ∼80% efficiency. The TaqTth-hpRNA cleavage of genomic DNA in mammalian cells...

This study investigates how amyloid pathology influences hippocampal-prefrontal neural dynamics and decision-making in Alzheimer's disease (AD) using 5XFAD mice, a well-established model system characterized by pronounced early amyloid pathology. Utilizing ecologically relevant "approach food-avoid predator" foraging tasks, we show that 5XFAD mice exhibit persistent risk-taking behaviors and reduced adaptability to changing threat conditions, indicative of impaired decision-making....

Imaging genomics offers powerful links between genetics and neuroimaging phenotypes, but conventional methods often lack spatial correspondence. We introduce spatial imaging-transcriptomics, a paradigm that directly integrates magnetic resonance imaging (MRI) and spatially resolved transcriptomics (ST) with matched resolution from the same brain through spatially co-registered maps. We apply this framework to wild-type and Alzheimer's disease (AD) mouse models to uncover the molecular...

Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN. Parkin-expressing U2 osteosarcoma (U2OS) cells were treated with the depolarizing agents oligomycin and antimycin A (OA) and subjected to cryo-focused ion beam milling and in situ cryo-electron tomography. Mitochondria were fragmented and devoid of matrix calcium phosphate crystals. Phagophores were visualized, with bridge-like...

Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We...

Parkinson's disease is characterized by loss of dopamine neurons that project to the dorsal striatum, and mutations in LRRK2 and GBA1 are the most common genetic causes of familial Parkinson's disease. Previously, we showed that pathogenic LRRK2 mutations inhibit primary cilia formation in rare interneurons and astrocytes of the mouse and human dorsal striatum. This blocks Hedgehog signaling and reduces synthesis of neuroprotective GDNF and NRTN, which normally support dopamine neurons...

The rising prevalence of Alzheimer's disease (AD) due to an aging population has made the search for effective treatments more urgent than ever. Previous studies have demonstrated that continuous ultrasound can depolymerize amyloid proteins, offering potential relief from AD. In this study, we present a portable, fully integrated wearable ultrasound system designed to promote amyloid protein depolymerization. The system comprises a flexible honeycomb ultrasonic array patch, a flexible printed...

Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer's disease (AD). To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer...

Cerebrovascular dysfunction underlies many neurological disorders, yet how genetic variants in brain vascular cells drive disease risk remains unknown. We developed MultiVINE-seq to simultaneously profile RNA and chromatin accessibility in vascular, perivascular, and immune cells from 30 human brains. Mapping genome-wide association study (GWAS) data to our multi-omic atlas linked thousands of GWAS disease-risk variants to target cell types and genes, including 2,605 previously unmapped. We...

ER and mitochondrial stress are often interconnected and considered major contributors to aging as well as neurodegeneration. Coordinated induction of ER^(UPR) and mito^(UPR) has been observed in diabetes and pulmonary disorders. However, in the context of aging and neurodegeneration, regulation of this intra-organellar crosstalk has remained relatively elusive. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial protein, accumulates at the ER-mitochondrial contact...

Physiological brain aging is associated with cognitive impairment and neuroanatomical changes. Brain age prediction of routine clinical 2D brain MRI scans were understudied and often unsuccessful. We developed a novel brain age prediction framework for clinical 2D T1-weighted MRI scans using a deep learning-based model trained with research grade 3D MRI scans mostly from publicly available datasets (N = 8681; age = 51.76 ± 21.74). Our model showed accurate and fast brain age prediction on...

The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on organ aging. Here, we demonstrate that both transgenic Alzheimer's disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits. Senescent BMAds acquire a secretory phenotype, markedly increasing secretion of serum amyloid P component (SAP), also...

The fruit fly Drosophila melanogaster emerges as an affordable, genetically tractable model of behavior and brain diseases. However, despite the surprising level of evolutionary conservation from flies to humans, significant genetic, circuit-level, and behavioral differences hinder the interpretability of fruit fly models for human disease. Therefore, to allow a more direct fly-versus-human comparison, we surveyed the rarely exploited, rich behavioral repertoire of fruit flies with genetic...