Alzheimer & Parkinson

No abstract

APOE4 is the primary risk factor for Alzheimer disease (AD). Early AD pathological events first affect the neuronal endolysosomal system, which in turn causes neuronal protein aggregation and cell death. Despite the crucial influence of lysosomes upon AD pathophysiology, and that APOE4 localizes to lysosomes, the influence of APOE4 on lysosomal function remains unexplored. We find that expression of APOE4 in neuronal cell lines results in lysosomal alkalinization and impaired lysosomal function....

Parkinson's disease (PD) has been associated with alterations in neuronal activity in the basal ganglia-thalamocortical (BGTC) network. Previous studies have suggested that cortical disinhibition is a feature of PD, but there has been little direct evidence of the changes in cortical neuronal spiking activity to support this hypothesis. To test the hypothesis that activity in the motor cortex is enhanced in PD, we investigated the effects of parkinsonism on movement-related neuronal activity in...

Parkinson's disease (PD) is a most common neurodegenerative disorder caused by genetic, epigenetic, and environmental factors. DNA methylation, regulated by DNA methyltransferases (DNMTs) is the key epigenetic modification playing an important role in gene expression regulation. Oligomeric alpha-synuclein - a major neurotoxic agent in PD - could sequester DNMT1 from the cell nucleus to the cytoplasm leading to global DNA hypomethylation. Here we evaluated DNMT1 expression (mRNA, protein),...

Parkinson's disease (PD) is being increasingly recognized for its complex clinical symptoms, including cognitive impairment, which are linked to dynamic changes in brain network configuration and genetic susceptibility. However, the time-varying patterns of network reconfiguration in patients with PD and their relationship with gene expression profiles and cognitive function remain unclear. To address this gap, we analyzed modular variability (MV) in time-varying brain networks-comparing group...

Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD...

No abstract

Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolaemia, explained by its ability to control hepatic output of lipoproteins. Although SORT1 also shows genome-wide association with Alzheimer disease and frontotemporal lobe dementia, the most prevalent forms of age-related dementias, sortilin's contribution to human brain lipid metabolism and health remains unclear. Here we show that sortilin mediates neuronal uptake of polyunsaturated fatty acids...

Deep brain stimulation (DBS) effectively treats drug-resistant neurological and psychiatric disorders, yet its mechanisms remain unclear. Here we show that high-frequency DBS of the subthalamic nucleus (STN), a common target for Parkinson's disease (PD), activates afferent axons while inhibiting STN neurons. These contrasting presynaptic and postsynaptic effects arise from a decrease in local neurotransmitter release with a larger decrease in glutamate than GABA, shifting the...

Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic...

No abstract

Endocytosis generates life-essential vesicles via complex protein-lipid machinery, yet its initiation mechanisms remain elusive. Long thought to require full machinery spatiotemporal coordination to drive the flat-to-round vesicle transformations, we reveal a notably simple initiation mechanism in neuroendocrine chromaffin cells involving only the final step, the pore closure. During calcium-triggered exocytosis, calcium activates the phosphatase synaptojanin, rapidly converting PI(4,5)P(2) to...

Neuroinflammation contributes to Alzheimer's disease (AD), but the molecules and pathways that initiate inflammation are unclear. In this issue of Immunity, Song et al. demonstrate that ZBP1-RIPK1 signaling in microglia can drive AD, wherein ZBP1 is activated by left-handed Z-DNA leaking from mitochondria, presenting new molecular targets for AD therapeutics.

In psychology and neuroscience, scientific questions are often framed in terms of mental activity (e.g., cognition, emotion, and perception); however, the brain is an organ with a particular function that only it can fulfill. Converging evidence suggests that this function is allostasis: the predictive regulation of competing demands from internal bodily systems. We review evidence for a distributed allostatic system that organizes whole-brain signaling, scaffolds psychological phenomena, and...

This systematic review investigates the timeline of Alzheimer's disease (AD)-like changes in the intracerebroventricular streptozotocin (ICV-STZ) rat model, a key tool for studying sporadic, non-genetic forms of AD. Following PRISMA guidelines, we analyzed 402 studies to characterize the progression of key pathological features, including cognitive deficits, insulin resistance, neurodegeneration, neuroinflammation, oxidative stress, tau pathology, amyloid aggregation, blood-brain barrier (BBB)...

Abnormal lipid metabolism is observed in Alzheimer's disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain's resident immune cells, influence lipid processing during AD. Here, we show that microglia-the brain's resident immune cells-selectively regulate lipid accumulation that associated with disease pathology in both AD mouse models and human postmortem brains. Using lipidomics and histological analysis, we identify a...

Parkinson's disease (PD) has long been considered an appropriate candidate for cell replacement therapy. We generated high-purity dopaminergic progenitors (A9-DPCs) from human embryonic stem cells and evaluated their safety and exploratory efficacy in a single-center, open-label, dose-escalation phase 1/2a trial (NCT05887466) for PD patients. Twelve patients with moderate-to-severe PD received bilateral putamen transplantation of low-dose (3.15 million cells; n = 6) or high-dose (6.30 million...

Galactocerebrosidase (GALC) is a lysosomal enzyme crucially involved in the catabolism of galactosphingolipids. Among galactosphingolipids, galactosylceramide and sulfatide are crucial determinants for oligodendrocyte differentiation, as well as myelin stability and structure. Homozygous or compound heterozygous inherited mutations leading to a severe decrease in GALC enzymatic activity have been associated with the onset of Krabbe disease, also known as "globoid cell leukodystrophy". Extensive...

The sensory motor cortex (SMC) plays a crucial role in motor function and is implicated in the pathophysiology of idiopathic Parkinson's disease (iPD). Asymmetric motor symptomatology in iPD suggests lateralized neurochemical alterations that may underlie disease progression and severity. Single-voxel in vivo proton magnetic resonance spectroscopy using PRESS (20 × 20 × 20 mm³) and MEGA-PRESS (30 × 30 × 30 mm3) sequences were performed on bilateral SMC in 25 iPD patients and 23 healthy controls...

Biological phenotypes emerge from complex interactions across molecular layers. Yet, data-driven approaches to infer these regulatory networks have primarily focused on single-omic studies, overlooking inter-layer regulatory relationships. To address these limitations, we developed MINIE, a computational method that integrates multi-omic data from bulk metabolomics and single-cell transcriptomics through a Bayesian regression approach that explicitly models the timescale separation between...