Alzheimer & Parkinson

Alzheimer's disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice....

Real-time in vivo monitoring of levodopa pharmacokinetics is essential to address its narrow therapeutic window in Parkinson's disease (PD) therapy. However, current methods require excessive sample volumes, suffer low sampling frequencies, and fail to capture complete pharmacokinetic profiles. Here, we present an in vivo monitoring system for real-time tracking of levodopa levels in interstitial fluid (ISF) using a spindle-shaped carbon nanotube (CNT) fiber electrochemical sensor functionalized...

Hundreds of human kinases, including PINK1-a protein kinase associated with familial Parkinson's disease-are regulated by Hsp90 and its cochaperones. While previous studies have elucidated the mechanism of kinase loading into the Hsp90 machinery, the subsequent regulation of kinases by Hsp90 and its cochaperones remains poorly understood. In this study, using complexes obtained through PINK1 pulldown, we determine the cryo-EM structures of the human Hsp90-Cdc37-PINK1 complex at 2.84 Å,...

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer's disease syndrome. 'Evaluating liraglutide in Alzheimer's disease' (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer's disease syndrome with no diabetes. Participants received...

Monoclonal antibodies approved for Alzheimer's disease (AD), such as lecanemab and aducanumab, have been shown to enhance microglial phagocytic function, underscoring the therapeutic relevance of microglia in neurodegenerative diseases (NDDs). Emerging evidence implicates lipid droplets (LDs) in brain aging and NDDs, particularly through LDs-laden microglia known as lipid droplet-accumulating microglia (LDAM), which exhibit impaired phagocytosis, elevated oxidative stress, and dysregulated lipid...

Emerging evidence highlights the crucial role of peripheral immune cells in maintaining brain homeostasis and their influence on the pathology of Alzheimer disease (AD). Genome-wide association studies have identified numerous AD risk variants in genes expressed by immune cells, implicating innate and adaptive immune pathways in disease progression. Advances in neuroimmunology have revealed that immune cell crosstalk involving T cells, B cells, monocytes and/or macrophages and neutrophils can...

Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2,...

Neural hyperexcitability and network dysfunction are neurophysiological hallmarks of Alzheimer's disease (AD) in animal studies, but their presence and clinical relevance in humans remain poorly understood. We introduce a perturbation-based approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG), alongside resting-state EEG (rsEEG), to investigate neurophysiological basis of default mode network (DMN) dysfunction in early AD. While rsEEG revealed global neural...

Intermittent fasting (IF) offers a potential strategy to counteract Alzheimer's disease (AD) progression. In our 16-week study on AD transgenic mice, IF positively affected cognitive function and reduced amyloid-β (Aβ) accumulation, verifying the IF's role in modulating neuroinflammation. Multiomics integration revealed strong links between IF-induced hippocampal gene expression, gut microbiota, and serum metabolites beneficial for cognition. Indole-3-propionic acid (IPA) emerged as a pivotal...

Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD^(+)) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic - transcriptional mechanism linking...

This review delves into the intricate relationship between serotonin signaling, mitophagy and mitochondrial dysfunction in Alzheimer's disease (AD), with a focus on the mechanistic pathways that link these processes and their potential therapeutic implications. A neurodegenerative condition called Alzheimer's disease is marked by cognitive deterioration. It is increasingly recognized as being influenced by impaired mitochondrial function and mitophagy, the selective degradation of damaged...

Alzheimer's disease (AD), the most common cause of dementia, is characterized by amyloid-β deposition, tau hyperphosphorylation, neuroinflammation, and progressive neuronal loss, with no curative therapy currently available. Dental pulp stem cells (DPSCs) derived from third molars represent an ethically accessible, minimally invasive, neural crest-derived mesenchymal stem cell source with self-renewal and multi-lineage differentiation potential. Preclinical evidence suggests that DPSCs exert...

The cerebellum, essential for motor coordination and increasingly recognized for its role in cognition, is typically considered more resilient to aging and largely spared from hallmark Alzheimer's disease (AD) pathology. However, transcriptomic analyses across fifteen mouse brain regions revealed that the cerebellum undergoes some of the earliest and most pronounced age-related changes. To investigate cerebellar aging, we applied single-nucleus RNA sequencing (RNA-seq), microglial bulk RNA-seq,...

CONCLUSION: Exercise can simultaneously impact insulin resistance and Alzheimer's disease pathology in animal models. Results from human research are limited, and no robust evaluation of the potential mediating role of insulin resistance in the physical activity - Aβ or tau relationship exists. Future research should focus on identifying the mediating pathways that may link physical activity to biomarkers of Alzheimer's disease.

Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of...

Genome-wide association studies have identified many loci for brain disorders, but most non-coding variants fail to colocalize with bulk expression quantitative trait loci. Single-cell expression quantitative trait loci studies capture cell-type-specific regulation but are often underpowered. We developed Bulk And Single cell expression quantitative trait loci Integration across Cell states (BASIC) to combine bulk and single-cell expression quantitative trait loci through "axis-quantitative...

Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly...

Intraneuronal aggregates of the microtubule-associated protein tau play a pivotal role in Alzheimer's disease and several other neurodegenerative syndromes. Anti-tau antibodies can reduce pathology in mouse models of neurodegeneration and are currently being tested in humans. Here, we performed a large-scale seroepidemiological search for anti-tau IgG autoantibodies (ατ) on 40,497 human plasma samples. High-titer ατ+ individuals were surprisingly prevalent, with hospital patients being three...

The abnormal protein degradation implicated in the pathogenesis of Parkinson's disease was previously attributed to defective H+ leakage from lysosomes via TMEM175 (https://doi.org/10.1016/j.cell.2022.05.021). In this issue, Riederer et al. (https://doi.org/10.1083/jcb.202501145) demonstrate that TMEM175 is instead a K+ channel, minimally permeable to H+.

Parkinson's disease (PD) is an increasingly prevalent neurodegenerative disorder, largely sporadic in origin, with limited understanding of age- and region-specific lipid alterations in the human brain. Dysregulation of glycosphingolipid catabolism has been implicated in PD, yet comprehensive spatiotemporal profiling remains sparse. Here, we performed targeted lipidomics across eight anatomically distinct brain regions in post-mortem controls, mid-stage, and late-stage PD cases using...