Alzheimer & Parkinson

The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer's disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and APP^(NL-G-F) mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization...

Prime editing offers versatile genome modifications with therapeutic potential; yet its use to modulate neural circuitry remains underexplored. Here, we used adeno-associated viral vectors to deliver prime editors into the mouse brain and introduced the naturally occurring Adrb1^(A187V) variant of the β1-adrenergic receptor, linked to short sleep in humans and mice. Editing reached up to 28.1% in the cortex six months after intracerebroventricular injection and increased excitability of...

UBB^(+1), a ubiquitin variant protein resulting from a frameshift in the ubiquitin-B gene, is a pathological hallmark of Alzheimer disease (AD). At the cellular level, UBB^(+1) disrupts the ubiquitin-proteasome system while inducing autophagy. Notably, UBB^(+1) itself is secreted via autophagosome-like vesicles. Here, we demonstrate that UBB^(+1) can be removed from the cell by degradative and secretory autophagy. Sequestosome 1 (SQSTM1)/p62 functions as a pivotal ubiquitin receptor for...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal cell death, brain atrophy, and cognitive decline. Aggregation of Tau protein in neurons is a critical factor in the pathogenesis of AD. Tau aggregates increase as the disease progresses and contribute to neuronal cell death. This study investigated the role of ubiquitin-specific protease 10 (USP10) in Tau pathology and neuronal viability in AD. We found that the expression of USP10 was reduced in the...

The glymphatic system was initially considered as a perivascular channel, responsible for the clearance of substances within the brain. With the deepening comprehension of the functions of the extracellular space (ECS) and the discovery of meningeal lymphatic vessels and subarachnoid lymphatic-like membrane, it is proposed that the glymphatic system should be a complex system encompassing the perivascular space, ECS, and lymphatic-like structures, and it plays crucial roles in the delivery of...

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is marked by dopaminergic neuron loss and α-synuclein aggregation. Although Braak staging based on Lewy body pathology stratifies disease progression, clinical variability persists. Identifying stage-specific molecular signatures is essential for developing effective progressive biomarkers. Here, we integrated midbrain transcriptomic data from microarray, bulk RNA-seq, and snRNA-seq platforms. Subsequently, to...

No abstract

Chaperone-mediated autophagy (CMA), once considered a secondary or auxiliary degradation pathway, is now recognized as a central regulator of synaptic proteostasis. A recent study by Khawaja et al. (2025) in Nature Cell Biology provides compelling evidence that CMA actively remodels the synaptic proteome in a sex-specific manner. Using a conditional knockout strategy based on Lamp2a-floxed mice crossed with a Camk2a-Cre driver line to achieve excitatory neuron-specific deletion of Lamp2a in...

Replicability analysis is a cornerstone for identifying genuine genetic associations in genome-wide association studies (GWAS), yet existing methods are constrained by their failure to account for linkage disequilibrium (LD) structure among single nucleotide polymorphisms (SNPs) or underuse of auxiliary information, limiting their reliability and statistical power. We develop CARLIS, a comprehensive covariate-assisted replicability analysis method to enhance both statistical rigor and biological...

Timely and accessible tools for detecting preclinical Alzheimer's disease (AD) are essential for early intervention, yet reliance on MRI biomarkers limits scalability. Using longitudinal data from 210 cognitively normal older adults in ADNI, we compared the predictive value of verbal episodic memory, hippocampal volume, and a visuospatial composite. Over a 7-year window, 106 participants progressed to mild cognitive impairment (MCI), while 104 remained stable. At baseline, Immediate Recall on...

CONCLUSIONS: The efficacy and safety of anti-amyloid mAbs in AD may differ based on patients' demographic and genetic factors. These findings highlight the potential for personalised treatment strategies and inform national drug policies. Further research is needed to evaluate long-term outcomes and address under-studied patient populations.

The brain is a metabolically vulnerable organ as neurons have both high resting metabolic rates and the need for local rapid conversion of carbon sources to ATP during activity. Midbrain dopamine neurons are thought to be particularly vulnerable to metabolic perturbations, as a subset of these are the first to undergo degeneration in Parkinson's disease, a neurodegenerative disorder long suspected to be in part driven by deficits in mid-brain bioenergetics. In skeletal muscle, energy homeostasis...

Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant...

CONCLUSION: The 95+-year-old population exhibits distinctive patterns of disease burden that have shifted substantially over the past three decades. Despite cross-national differences, cardiometabolic diseases and risk factors, along with multisystem comorbidities from the brain and kidneys, remain the primary drivers. Integrated strategies addressing biological, social, and environmental factors may enhance intrinsic capacity and promote healthy aging in the oldest old.

The role of estradiol in depression and Alzheimer's disease - brain disorders that disproportionately affect females - is debated. Results from observational studies are inconsistent and limited by confounding and reverse causation. To overcome these limitations, we perform two-sample Mendelian randomization. We run genome-wide association studies on sex-specific brain age gap, a proxy of brain health, and female-specific estradiol levels using data from the UK Biobank. We test for causal links...

Auditory gamma stimulation is a promising non-invasive neuromodulation technique for cognitive decline, with preclinical studies demonstrating therapeutic effects in Alzheimer's disease models. However, translating these findings into human trials has produced variable outcomes, suggesting a need to examine factors influencing efficacy. In a systematic review of 62 studies on healthy and cognitively impaired populations, we identified 16 characteristics that may affect the response to...

In this issue of Neuron, Luo et al.¹ report two supramammillary neuronal populations with segregated projections to the dorsal and ventral dentate gyrus that selectively modulate cognitive and emotional processes, respectively. Targeted activation of each pathway alleviates domain-specific behavioral deficits in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia. Cellular senescence, widely acknowledged as a key hallmark of aging, has increasingly been recognized as a significant factor in the pathogenesis of AD, although the precise mechanisms underlying this relationship have yet to be fully understood. In the brains of individuals with AD, neurons, glial cells, and cerebrovascular endothelial cells exhibit premature senescence, characterized by...

Major depressive disorder (MDD) is linked to a higher risk of premature aging, but the mechanisms underlying this association remain unclear. Using data from two population cohorts (UK Biobank and Finnish Twin Cohort), we evaluate the relationship between systemic and organ-specific proteomic and epigenetic aging acceleration and MDD. A lifetime history of MDD was associated with accelerated proteomic aging at both systemic and organ-specific levels-including the brain-in both cohorts, with...

Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid β (Aβ) deposition, and synaptic dysfunction. However, the mechanisms underlying neurodegeneration remain poorly understood. In this study, we investigated the therapeutic potential of PBX1, a transcriptional regulator implicated in neurodevelopment and neuroprotection, against AD. PBX1 expression was significantly downregulated in postmortem hippocampal tissues from patients with AD and in the APP/PS1 mouse...