Alzheimer & Parkinson

Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present a transcriptional analysis of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, such as 63 patients representing the full clinical and...

Parkinson's Disease (PD) is an incurable neurodegenerative disease that causes movement disorders. Neurons in PD aggregate α-synuclein and are depleted from the substantia nigra (SN), which is a movement control hub. The presence of α-synuclein-reactive T cells in PD patient blood suggests a role for adaptive immunity in the pathogenesis of PD. However, the characteristics of this response within the brain are not well understood. Here, we employed single-nucleus RNAseq, spatial transcriptomics,...

Caloric restriction slows or prevents Alzheimer's disease in animal models. Calorie restriction is typically implemented in rodents through feeding once per day; as the animals quickly consume their food, they are subject to a prolonged self-imposed fasting period between meals. Here, we examine the distinct contributions of fasting and reduced calories to the beneficial effects of calorie restriction on Alzheimer's disease by placing male and female 3xTg and non-transgenic control mice on a...

Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is...

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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...