Alzheimer & Parkinson

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. It is associated with the ongoing degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that contain α-synuclein. These pathological changes lead to abnormalities of motor symptoms (tremor, rigidity, bradykinesia) and non-motor symptoms (cognitive decline, sleep abnormalities, psychiatric abnormalities). The pathogenesis of PD is complex and multifactorial,...

Human-induced pluripotent stem cell-derived midbrain organoids offer a promising platform for modeling Parkinson's disease (PD). Yet, their utility has been limited by the absence of microglia and the development of a necrotic core during maturation. Here, we present an air-liquid interface (ALI) slice culture system for extended cultivation of midbrain organoids (mORGs), enabling efficient microglial integration, improved neuronal viability, and enhanced functional maturation. Compared with...

Cerebrovascular and neurodegenerative diseases rank among the leading causes of death worldwide and represent an increasing socioeconomic burden, particularly in aging populations. Pluripotent stem cell (PSC)-based therapies have emerged as promising strategies for replacing lost neurons and restoring neural circuits in disorders of the central nervous system (CNS). However, major barriers remain, including poor survival, limited integration, and variable functional maturation of transplanted...

Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33^(M) splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33^(M) ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33^(M), but...

The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts...

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, yet its transcriptional regulatory architecture remains poorly understood. Here, we model sample-specific gene regulatory networks (GRNs) from dorsolateral prefrontal cortex transcriptomes of 87 individuals with AD and 67 non-cognitively impaired (NCI) controls and use a machine learning classifier to detect consistent disease-specific network features. This sample-specific network...

Proteostasis collapse, a hallmark of aging and neurodegeneration like Alzheimer's disease (AD), causes irreversible damage in late life. Whether late-life proteostasis capacity is developmentally programmed remains unclear, as mechanistic studies requiring lifelong tracking and molecular manipulation are challenging or impossible in long-lived species. Using C. elegans as a lifelong, genetically tractable AD model, we uncover a critical early-life window during which reducing TIP60/NuA4...

The aggregation of α-synuclein (αSyn), a 140-mer protein, has been implicated in the pathogenesis of Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. KTKEGV pseudo-repeats (KRs) in the sequence of αSyn are key mediators of its prion-like propagation and neurodegeneration. Despite the availability of symptomatic treatments, no current therapy effectively delays disease progression. Here we report a 77-nucleotide RNA aptamer called 1R6, obtained through in vitro...

Genomic studies at single-cell resolution have identified several cell types associated with clinical and pathological traits in Alzheimer's disease^(1-9), but have not examined associations that are shared across populations. To bridge this gap, here we use single-nucleus RNA sequencing and assay for transposase-accessible chromatin with sequencing to profile cortical and subcortical regions in post-mortem brain-tissue samples from Latin, white (excluding Latin) and African American (excluding...

While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new...

Maximizing clinical benefits of therapeutics while minimizing adverse effects is a central challenge in drug development. For Parkinson's disease (PD), l-3,4-dihydroxyphenylalanine (l-dopa) is the most effective treatment available, but chronic use is associated with periods of reduced efficacy (motor fluctuations) and the debilitating on-target side effect of l-dopa-induced dyskinesia. To disentangle the molecular mechanisms underlying l-dopa's antiparkinsonian effects versus its dyskinetic...

The basal ganglia are characterized by somatotopic representation and are organized in parallel, functionally segregated corticostriatal circuits, but the impact of Parkinson's disease (PD) on this architecture is unknown. We mapped task-evoked dopamine release using [^(11)C]raclopride positron emission tomography/magnetic resonance in 13 early PD and 15 healthy control (HC) subjects during the performance of motor, cognitive, and reward tasks. In PD, motor tasks elicited decreased relative...

Inflammasomes, particularly the NLRP3 complex, play a central role in coordinating innate immune activation and neuroinflammatory responses within the cytosol. Persistent or dysregulated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) activation promotes caspase-1-dependent maturation of interleukin (IL)-1β and IL-18 and triggers gasdermin D (GSDMD)-mediated pyroptosis, thereby contributing to the pathogenic cascades underlying Alzheimer's disease...

This longitudinal study including four independent cohorts assessed the spatiotemporal dynamics of tau extent and load changes in Alzheimer's disease using tau positron emission tomography data from 2,459 participants, including 898 followed for up to 7 years. Regional standardized uptake value ratios indexed tau load, whereas the spatial extent of tauopathy (SEOT) (proportion of abnormal voxels) measured tau extent. We observed burden-dependent longitudinal dynamics of tau progression: SEOT...

α-Synucleinopathies are devastating neurodegenerative diseases characterized by pathological accumulation of a neuronal protein, α-synuclein (αSyn). Lowering soluble αSyn levels is a promising therapeutic strategy to limit aggregation and neurotoxicity, but directly targeting this protein is hindered by its intrinsically disordered structure and other factors, such as its conformational heterogeneity and intracellular drug delivery barriers. Consequently, increasing attention has been directed...

Central to Alzheimer's disease pathology are prefibrillar oligomer assemblies of amyloid-β (Aβ) peptide. A widely discussed hypothesis proposes that amyloid-β oligomers insert into neuronal lipid membranes, disrupting their integrity and causing a loss of cellular homeostasis in Alzheimer's disease. This membrane disruption is believed to be a major source of Aβ-induced neurotoxicity. Cryo electron tomography (cryo-ET) has facilitated 3D nanoscale imaging of Aβ-membrane interactions under...

High levels of mitochondrial DNA (mtDNA) deletions have been described in the substantia nigra. However, the mechanisms involved are poorly understood. We found that transient expression of a mitochondrial targeted restriction endonuclease (mitoPstI) in mice leads to an accumulation of mtDNA rearrangements that involve both the PstI cleavage sites and unrelated specific regions of the mtDNA, including the MTERF1 binding site and the edge of the D-loop. This pattern of rearrangements after...

Alzheimer's disease (AD) is a multifactorial disorder involving various pathological mechanisms, such as amyloidosis, immune dysfunctions, and synaptic impairments, which are important therapeutic targets. Repurposing drugs to target these mechanisms offers a promising approach to reduce the costs and duration of drug development. Genetic studies underscore the critical role of microglial clearance of amyloid-beta (Aβ) in AD pathogenesis. Specifically, soluble ST2 (sST2)-one of the two major...

We present CIT-Lasso, a framework that uses only summary statistics to identify, genome-wide, sets of variants carrying non-redundant information on a phenotype, distinguishing likely causal variants from correlated variants that are merely associated. The open-source implementation completes genome-wide analysis in under 15 min on one CPU. In simulations, it outperforms existing methods in false discovery rate control, power, and fine-mapping resolution. Applied to an Alzheimer's disease...

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive impairments in episodic and spatial memory, as well as circuit and network-level dysfunction. While functional impairments in medial entorhinal cortex (MEC) and hippocampus (HPC) have been observed in patients and rodent models of AD, it remains unclear how communication between these regions breaks down in disease, and what specific physiological changes are associated with the onset of memory impairment. Here,...