Alzheimer & Parkinson

Self-replicating amyloid beta (Aβ) oligomers are considered as one of the major drivers for disrupted synaptic function and plasticity, leading to impaired neuronal viability and progression of Alzheimer's disease (AD). Here, we investigated the safety, tolerability and pharmacokinetics of the anti-oligomeric peptide PRI-002, which was developed to disassemble toxic Aβ oligomers into non-toxic monomers. In a randomized, double-blind, single-center phase 1b trial, 20 patients aged between 50 and...

Mitochondrial dysfunction plays a preponderant role in the development of Alzheimer disease (AD). We have demonstrated that activation of PINK1 (PTEN induced kinase 1)-dependent mitophagy ameliorates amyloid pathology, attenuates mitochondrial and synaptic dysfunction, and improves cognitive function. However, the underlying mechanisms remain largely unknown. Using a newly generated PINK1-AD transgenic mouse model and AD neuronal cell lines, we provide substantial evidence supporting the...

Parkinson's disease (PD) is a neurodegenerative disorder characterised by motor and non-motor symptoms. Recent evidence suggests a role for gut microbiome composition and diversity in PD aetiology. This study aimed to explore the association between the gut microbiome and PD in a South African population. Gut microbial sequencing data (cases: n = 16; controls: n = 42) was generated using a 16S rRNA gene (V4) primer pair. Alpha- and beta-diversity were calculated using QIIME2, and differential...

Voxel-based morphometry (VBM) and surface-based morphometry (SBM) based on magnetic resonance structural imaging were used to identify disease progression in mild cognitive impairment (MCI) patients. A retrospective analysis was conducted on 154 MCI patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, with 62 patients classified into the progressive MCI (pMCI) group and 92 patients into the stable MCI (sMCI) group. VBM and SBM were employed to identify structural...

Autophagy is a pro-survival process that regulates the degradation and renewal of cellular components, making it a crucial mechanism for cellular homeostasis. There are selective forms of autophagy that are specific to a number of substrates, such as pathogens (bacteria or viruses), protein aggregates or excess/damaged organelles. These processes involve as key players autophagy receptors, that link the cargo to be degraded to the autophagic machinery. Among them, NDP52 (also known as CALCOCO2)...

Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease (PD). Through a high-throughput screen, we recently identified 38 genes whose knockdown modulates αSyn propagation. Here, we show that, among those, TAX1BP1 regulates how αSyn interacts with lipids, and ADAMTS19 modulates how αSyn phase separates into inclusions, adding to the growing body of evidence implicating those processes in PD. Through RNA sequencing, we...

The ability to transplant immunologically foreign cells into an animal without immune suppression would be transformative. Pavan et al. show that human pluripotent stem cell-derived dopaminergic neuron progenitors engineered to express eight immune-evasive proteins can engraft in humanized mice and a rat model of Parkinson's disease without recourse to immune suppression.¹.

Transplantation of human fetal ventral mesencephalic tissue in individuals with Parkinson's disease has yielded clinical benefits but also side effects, such as graft-induced dyskinesias. The open-label TransEuro trial ( NCT01898390 ) was designed to determine whether this approach could be further developed into a clinically useful treatment. Owing to poor availability of human fetal ventral mesencephalic tissue, only 11 individuals were grafted at two centers using the same tissue preparation...

Recent advances have shown that single-nucleus RNA sequencing (snRNA-seq) can be applied to formalin-fixed, paraffin-embedded (FFPE) tissues, opening avenues for transcriptomic analysis of archived specimens. Yet, isolating intact nuclei remains difficult due to RNA cross-linking. Here, we introduce a cryogenic enzymatic dissociation (CED) strategy for rapid, high-yield and fidelity nuclei extraction from FFPE samples and validate its utility with snRandom-seq (snCED-seq) using male C57/BL6...

Microglia and border-associated macrophages (BAMs) are critical for brain health, and their dysfunction is associated to disease. Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Here, we demonstrate that monocytes can efficiently replace all brain macrophages. Monocytes readily replaced embryonal BAMs upon their depletion and engrafted as monocyte-derived microglia (Mo-Microglia) upon more sustained niche availability. Mo-Microglia expanded comparably...

Genetic studies implicate clusterin (CLU) in the pathogenesis of Alzheimer's disease (AD), yet its precise molecular impact remains unclear. Through unbiased proteomic profiling and functional validation in CLU-deficient astrocytes, we identify increased nuclear factor κB (NF-κB)-dependent signaling and complement C3 secretion. Reduction of astrocyte CLU induced microglia-dependent modulation of extracellular apolipoprotein E (APOE) and phosphorylated tau, as well as increased microglial...

Neurotransmitter release occurs through exocytosis of synaptic vesicles. α-Synuclein's function and dysfunction in Parkinson's disease and other synucleinopathies is thought to be tightly linked to synaptic vesicle binding. Age is the biggest risk factor for synucleinopathy, and ~15% of synaptic vesicle proteins have been linked to central nervous system diseases. Yet, age- and disease-induced changes in synaptic vesicles remain unexplored. Via systematic analysis of synaptic vesicles at the...

The differentiation of human pluripotent stem cells (hPSCs) provides access to a wide range of cell types and tissues. However, hPSC-derived lineages typically represent a fetal stage of development, and methods to expedite the transition to an aged identity to improve modeling of late-onset disease are limited. In this study, we introduce RNAge, a transcriptome-based computational platform designed to enable the evaluation of an induced aging or a rejuvenated state. We validated this approach...

In Alzheimer's disease, amyloid beta (Aβ) and tau pathology are thought to drive synapse loss. However, there is limited information on how endogenous levels of tau, Aβ and other biomarkers relate to patient characteristics, or how manipulating physiological levels of Aβ impacts synapses in living adult human brain. Using live human brain slice cultures, we report that Aβ(1-40) and tau release levels vary with donor age and brain region, respectively. Release of other biomarkers such as KLK-6,...

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Growing genetic and pathological evidence has identified microglial dysfunction as a key contributor to the pathogenesis and progression of various neurological disorders, positioning microglia replacement as a promising therapeutic strategy. Traditional bone marrow transplantation (BMT) methods for replenishing brain microglia have limitations, including low efficiency and the potential for brain injury because of preconditioning regimens, such as irradiation or chemotherapy. Moreover,...

Alzheimer's disease is a debilitating neurodegenerative disorder with no cure and few treatment options. In early stages of Alzheimer's disease, impaired metabolism and functional connectivity of the retrosplenial cortex strongly predict future cognitive impairments. Therefore, understanding Alzheimer's disease-related deficits in the retrosplenial cortex is critical for understanding the origins of cognitive impairment and identifying early treatment targets. Using the 5xFAD mouse model, we...

The regulation of microglial dysfunction has become increasingly prominent in treatment of Alzheimer's disease (AD). Herein, we develop a scalable polymer-involved biomimetic assembly that responds to intracerebral reactive oxygen species (ROS) for elastic spreading and concentration-dependent drug therapy. Structurally, a polymer of thermally sensitive deformation is selected for hydrophobic loading of curcumin (Cur) and coordinative grafting onto ultrasmall ceria (CeO(2)) by elastic...

Tau accumulation is closely related to cognitive symptoms in Alzheimer's disease (AD). However, the cellular drivers of tau-dependent decline of memory-based cognition remain elusive. Here, we employed in vivo Neuropixels and patch-clamp recordings in mouse models and demonstrate that tau, independent of β-amyloid, selectively debilitates complex-spike burst firing of CA1 hippocampal neurons, a fundamental cellular mechanism underpinning learning and memory. Impaired bursting was associated with...

Epigenomic profiling of the brain has largely been done on bulk tissues, limiting our understanding of cell type-specific epigenetic changes in disease states. Here, we introduce cell type-specific histone acetylation score (CHAS), a computational tool for inferring cell type-specific signatures in bulk brain H3K27ac profiles. We applied CHAS to >300 H3K27ac chromatin immunoprecipitation sequencing samples from studies of Alzheimer's disease, Parkinson's disease, autism spectrum disorder,...