Alzheimer & Parkinson

Modulation of neuronal oscillations holds promise for the treatment of neurological disorders. Nonetheless, conventional stimulation in a continuous open-loop manner can lead to side effects and suboptimal efficiency. Closed-loop strategies such as phase-locked stimulation aim to address these shortcomings by offering a more targeted modulation. While theories have been developed to understand the neural response to stimulation, their predictions have not been thoroughly tested using...

Lipid nanoparticles have shown success in targeting major organs such as the liver, spleen, and lungs, but crossing the blood-brain barrier (BBB) remains a major challenge. Effective brain-targeted delivery systems are essential for advancing gene therapy for neurological diseases but remain limited by low transport efficiency and poor nucleic acid stability. Here, we report a library of ionizable lipids based on the tetrahydroisoquinoline structure of protoberberine alkaloids, designed to...

Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer's disease (AD), where they impair axonal electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human induced...

Alzheimer's disease (AD) is characterized by progressive cognitive decline, severe brain atrophy and neuroinflammation. We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 2a clinical trial that tested the safety and efficacy of laromestrocel, a bone-marrow-derived, allogeneic mesenchymal stem-cell therapy, in slowing AD clinical progression, atrophy and neuroinflammation. Participants across ten centers in the United States were randomly assigned 1:1:1:1 to four...

Microbial infection, the strong trigger to directly induce inflammation in brain, is long considered a risk factor of Alzheimer's disease (AD), but how these infections contribute to neurodegeneration remains underexplored. To examine the effect of herpes simplex virus type 1 (HSV-1) infection on tauopathy in local hippocampus of P301S mice, we utilized a modified HSV-1 strain (mHSV-1) potentially relevant to AD, we found that its infection promotes tau-related pathology in part via activating...

Parkinson's disease (PD) is the second most commonneurodegenerative disease, characterized bybradykinesia, resting tremor, stiffness, and postural instabilityresulting due to the progressive loss ofdopaminergic neurons in the substantia nigra (SN). The pathophysiology of PDis extremely complex and involves mitochondrial dysfunction, oxidative stress, neuroinflammation, and disruption of protein homeostasis. Its progression is affected by both environmental and genetic factors, including...

Fraud undermines Alzheimer's disease research.

The Sociedad de Neurociencias del Uruguay is celebrating its 30th anniversary, sustained by more than a century of neuroscience research in the country. During this time, different approaches and experimental organisms have been incorporated to study diverse aspects of neurobiology. One of these experimental animals, successfully used in a variety of biological fields, is the fruit fly Drosophila melanogaster. Although Drosophila has been a model organism for neuroscience research worldwide for...

Hippocampal sclerosis (HS) is a pathological condition characterized by significant loss of hippocampal neurons and gliosis. This condition represents the most common neuropathological change observed in patients with temporal lobe epilepsy (TLE) and is also found in aging individuals. TLE related to HS is the most prevalent type of drug-resistant epilepsy in adults, and its underlying mechanisms are not yet fully understood. Therefore, developing improved methods for predicting and treating...

Revealing the temporal evolution of cerebrospinal fluid (CSF) biomarkers during aging is critical to understanding disease pathogenesis and developing early diagnoses and interventions for Alzheimer's disease (AD). CSF was obtained from 549 cognitively normal subjects between 18 and 93 years of age. 12 AD-related biomarkers were evaluated, including amyloid β (Aβ42, Aβ40, Aβ42/Aβ40 ratio), hyperphosphorylated tau (P-tau), neuronal injury/degeneration (T-tau, NFL, NSE, H-FABP, VILIP-1),...

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Despite its significant heritability, the genetic basis of Parkinson's disease (PD) remains incompletely understood. Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD (p = 6.1 × 10^(-7); odds ratio [95% confidence interval] = 10.5 [5.2, 21.3]). We replicate this association in three independent datasets totaling 8,407 cases and 413,432 controls...

Accurate diagnosis of early Parkinson's disease requires platforms suitable for detecting minute amounts of neuronally derived biomarkers in the massive protein excess of easily accessible biofluids such as blood. Here, we describe an on-chip droplet-confined fluorescence reporting assay that identified α-synuclein on the membrane of L1CAM+ extracellular vesicles (EVs) immunocaptured from human serum and corroborate this finding by super-resolution direct stochastic optical reconstruction...

In 2020, a case report described autologous transplantation of iPSC-derived dopamine (DA) neurons in a Parkinson's disease (PD) patient.¹ The team now follows up with the pre-clinical safety and efficacy data of autologous iPSC-derived DA neurons, forming the basis for regulatory approval of a phase 1 clinical trial involving 8 patients.².

Sleep loss is often regarded as an early manifestation of neurodegenerative diseases given its common occurrence and link to cognitive dysfunction. However, the precise mechanisms by which sleep disturbances contribute to neurodegeneration are not fully understood, nor is it clear why some individuals are more susceptible to these effects than others. This review addresses critical unanswered questions in the field, including whether sleep disturbances precede or result from neurodegenerative...

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A promising therapeutic intervention for preventing the onset and progression of Alzheimer's Disease (AD) is to protect and improve synaptic resilience, a well-established early vulnerability associated with the toxic effects of oligomers of Aβ (AβO) and Tau (TauO). We have previously reported that exosomes from hippocampal neural stem cells (NSCs) protect synapses against AβO. Here, we demonstrate how exosomes can also shield against TauO toxicity in adult mice synapses, potentially benefiting...

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A rare variant of Apolipoprotein E3 with neuroprotective properties has been identified in autosomal-dominant Alzheimer's disease. In this issue of Neuron, Chen et al.¹ show that direct interaction between this variant and tau blocks tau pathogenesis in rodent models.