Alzheimer & Parkinson

Deep brain stimulation (DBS) has garnered widespread use as an effective treatment for advanced Parkinson's disease. Conventional DBS (cDBS) provides electrical stimulation to the basal ganglia at fixed amplitude and frequency, yet patients' therapeutic needs are often dynamic with residual symptom fluctuations or side effects. Adaptive DBS (aDBS) is an emerging technology that modulates stimulation with respect to real-time clinical, physiological or behavioural states, enabling therapy to...

Mutations in the E3 ubiquitin ligase Parkin gene have been linked to early onset Parkinson's disease. Besides many other roles, Parkin is involved in clearance of damaged mitochondria via mitophagy-a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of...

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Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H^(+)-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive...

Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1...

Nucleocytoplasmic transport defects are observed in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here, we assess mRNA nucleocytoplasmic localization by performing transcriptome-wide profiling on nuclear and cytoplasmic fractions of human iPSC-derived cortical neurons from healthy individuals compared to those with familial AD or FTD. We find that AD- and FTD-causing mutations induce significant changes in mRNA nucleocytoplasmic distribution. We additionally observe the...

The basal ganglia play a crucial role in action selection by facilitating desired movements and suppressing unwanted ones. The substantia nigra pars reticulata (SNr), a key output nucleus, facilitates movement through disinhibition of the superior colliculus (SC). However, its role in action suppression, particularly in primates, remains less clear. We investigated whether individual SNr neurons in three male macaque monkeys bidirectionally modulate their activity to both facilitate and suppress...

The aggregation of α-synuclein into amyloid fibrils is a hallmark of Parkinson's disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the latter are present. Despite this importance, the molecular mechanisms of lipid-induced amyloid aggregation have remained largely elusive. Here, we present a global kinetic model to describe lipid-induced amyloid aggregation of α-synuclein. Using this framework, we find that α-synuclein fibrils form via...

The Christchurch mutation (R136S) in the APOE3 (E3S/S) gene is associated with attenuated tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high amyloid burden in the carrier. However, the molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse Apoe with wild-type human APOE3 or APOE3S/S on a tauopathy background. The R136S mutation decreased tau load and protected against tau-induced...

Neurodegenerative diseases activate innate and adaptive immune responses that can either slow or accelerate disease progression. Here, we sought to define beneficial immune pressures that emerge during tauopathy development in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of phosphorylated tau (pTau) in the central nervous system and blood. However, over time microglia converted into...

Alzheimer's disease (AD) is a neurocognitive disorder that affects a significant part of the population. Its symptoms include progressive loss of memory and executive dysfunction. Genetic susceptibility to AD can be influenced by allele variants of the APOE gene. On the other hand, lifelong experiences such as educational attainment, occupational complexity, and leisure activities, known proxies for cognitive reserve (CR), may modulate gene expression, ultimately impacting AD susceptibility. In...

The decline of adult neurogenesis and neuronal function during aging underlies the onset and progression of neurodegenerative diseases such as Alzheimer's disease. Conventional therapies, including neurotransmitter modulators and antibodies targeting pathogenic proteins, offer only symptomatic improvement. As the most abundant glial cells in the brain, astrocytes outnumber neurons nearly fivefold. However, their proliferative and transdifferentiation potential renders them ideal candidates for...

Alzheimer's disease (AD) is the main cause of dementia in the old-age population worldwide. AD is a progressive brain neurodegenerative disease due to genetic and environmental factors that induce the accumulation of intracellular hyperphosphorylated tau protein and extracellular amyloid protein (Aβ). Particularly, cholinergic neurons in the prefrontal cortex and hippocampus are mainly affected in AD, resulting in cognitive impairment and memory dysfunction. Therefore, restoration of cholinergic...

Changes in the transcriptome are critical in shaping the structural plasticity of neurons, which underpins learning and long-term memory storage. Here, we explored the effect of two opposing, plasticity-associated pathways-cAMP second-messenger signaling and metabotropic glutamate receptor (mGluR1 and mGluR5) signaling-on the transcriptome in hippocampal neurons and how these pathways operate in distinct and coordinated manners to induce structural changes. Integration of transcriptome data and...

Striatal cholinergic interneurons (SCINs) exhibit pause responses conveying information about rewarding events, but the mechanisms underlying these pauses remain elusive. Thalamic inputs induce a pause mediated by intrinsic mechanisms and regulated by dopamine D2 receptors (D2Rs), though the underlying membrane currents remain unknown. Moreover, the role of D5 receptors (D5Rs) has not been addressed so far. Here, we performed ex vivo studies showing that glutamate released by thalamic inputs in...

Over 20% of patients with Alzheimer's disease (AD) worldwide are Chinese, although the efficacy of existing blood-based measures of AD biomarkers is largely unknown in Asian cohorts. Here we explored how plasma tau biomarkers correlated with cross-sectional and longitudinal AD-related outcomes and their diagnostic performance in 1,085 participants from three independent studies, including two Chinese cohorts, Greater-Bay-Area Healthy Aging Brain Study (n = 425) and Huashan (n = 297), and the...

In this issue of Neuron, Son et al.¹ reveal how pathologic α-synuclein inhibits autophagy, leading to neurodegeneration. Their work highlights the key roles of the acetyl-CoA-producing enzyme ACLY and aberrant cytoplasmic p300 acetylation, uncovering new therapeutic strategies for Parkinson's disease.

Clusterin (CLU) is a recognized genetic risk factor for Alzheimer's disease. In this issue of Neuron, Lish et al.¹ found that lower CLU levels in astrocytes, caused by the CLU risk allele, heightened inflammation and reduced synaptic functions, potentially increasing risk for cognitive decline.

Saliva is an accessible biofluid with potential for non-invasive disease diagnostics. This study explores how genetic susceptibility to common diseases is reflected in DNA methylation (DNAm) and gene expression profiles in saliva. We constructed cis-mQTL (n = 345) and cis-eQTL (n = 277) datasets and examined correlations between DNAm and gene expression. Saliva QTLs were integrated with summary statistics from 36 genome-wide association studies (GWAS) using Summary-based Mendelian Randomization...

Cortical tau deposition begins in higher-order association regions and spreads to lower-order primary sensory-motor networks in moderate/advanced Alzheimer's dementia. The neural mechanisms underlying this spatiotemporal pattern remain elusive. Initial evidence has shown that coupled dynamic, low-frequency (<0.1 Hz) brain activity in cerebrospinal fluid (CSF) flow and gray matter (global brain-CSF coupling) might be related to CSF clearance and thus β-amyloid accumulation. Here, we report that...