Alzheimer & Parkinson

N-bridged [3.2.1]octanes (tropanes) and their related bridged bicyclic systems constitute highly sought-after scaffolds in drug discovery and development. Notably, the enantioselective synthesis of chiral 3-aryltropanes which are compounds widely distributed across bioactive pharmaceutical agents remains underdeveloped. Tropinone is a readily available and cost-effective starting material. By initiating the synthesis from tropinone, it is possible to substantially lower the synthesis costs. Here...

α-Synuclein conformational strains provide a potential explanation for the clinical and pathological differences among synucleinopathies such as Parkinson's disease and multiple system atrophy. However, how distinct α-synuclein strains arise remains unknown. Here, we observed conformational heterogeneity between individual preparations of α-synuclein pre-formed fibrils (PFFs) generated by polymerizing wild-type or A53T-mutant human α-synuclein under identical conditions. Moreover, we found that...

CONCLUSIONS: From 1990 to 2021, there was an overall upward trend in the global burden of ADOD among postmenopausal women. Driven by demographic shifts (population growth and aging) and metabolic risks (particularly high fasting plasma glucose), the burden of postmenopausal women with ADOD is expected to increase substantially. Postmenopausal women in higher SDI countries bore a disproportionately higher ADOD burden, and the SDI-related inequalities among countries widened during the study...

CONCLUSION: This multimodal analysis links PD-related ALFF and ReHo alterations to distinct yet converging transcriptomic, cellular, and neurochemical substrates. The findings suggest that PD-related functional alterations spatially align with glial-neurovascular transcriptional gradients and serotonergic receptor distribution, providing convergent but indirect evidence for their involvement in PD-related network reorganization.

Collinolactone, featuring a 7/10/6 tricyclic core, has been proposed to be biosynthesized via a transannular [6 + 4] cycloaddition reaction. Besides its intriguing architecture, collinolactone holds pharmaceutical promises due to its ability to disrupt amyloid-β (Aβ) and tau aggregation, which are specifically found as disease culprits in the brains of Alzheimer's disease (AD) patients and are key targets in current drug discovery efforts. However, challenges associated with its acquisition from...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, dementia, and ultimately death. Recent anatomical and functional discoveries of neuroimmune interactions during the development and progression of AD are beginning to shed light on disease mechanisms and potential precision immunotherapies. Here, we review the current understanding of the contribution of innate and adaptive immunity to AD pathogenesis and progression. We discuss how microglia...

Parkinson's disease (PD) is a complex neurodegenerative disorder with both genetic and environmental contributions. Over the past two and a half decades, advances in genetics, genomics and molecular biology have uncovered several monogenic forms of PD, linked to mutations in a number PD genes (collectively called PARK genes) such as SNCA, LRRK2, PRKN, PINK1, and DJ-1. To date there are 26 PARK genes reported with more than 100 genetic variants that increase the risk of PD. These genetic...

Alzheimer's disease (AD), the leading cause of dementia, is predominantly sporadic and influenced by non-genetic factors, including the gut microbiota. Cohabitation studies have shown microbial transmission between AD transgenic (Tg) and wild-type (WT) mice, leading to cognitive impairment; however, the mechanisms during early-life co-housing exposure remain largely undetermined. Here, one-month-old WT mice were housed with age-matched AD Tg (5XFAD) mice for 3 months. Gut microbiota composition...

Alzheimer's disease (AD) involves proteostasis dysregulation causing protein misfolding, but whether these structural changes manifest as plasma conformational biomarkers remains unclear. We profiled plasma protein structures from 520 participants including individuals with AD, individuals with mild cognitive impairment (MCI) and healthy controls. Using mass spectrometry and machine learning, we systematically characterized the structural proteome changes associated with ApoE variations and...

Alzheimer's disease has widespread effects on brain structure, function and behavior, but we lack a systematic dissection of its impact across hundreds of forebrain and brainstem regions. Here, using diffusion tensor MRI at 25 µm, we mapped the global consequences of mutations in APP and PSEN1 across 231 regions of interest (ROIs) in male and female 5×FAD BXD hybrid mice at 14 months. Over half of the ROIs change in volume along rostrocaudal and mediolateral axes of the CNS, with unexpected...

Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) are clinically heterogeneous, hampering the success of nonselective treatment strategies. Here we apply a transformer-based unsupervised clustering framework to longitudinal electronic health record data from over 100,000 patients across two UK cohorts, Clinical Practice Research Datalink Aurum and UK Biobank, to identify, validate and characterize subtypes of AD and PD. We uncover five reproducible subtypes...

The misfolding and accumulating α-synuclein (αSyn) is a central pathological hallmark of various neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Under physiological conditions, αSyn essential for normal synaptic functions primarily through its regulation of synaptic vesicle trafficking, clustering, and neurotransmitter release. However, in disease states, the accumulation of pathological αSyn disrupts intracellular proteostasis,...

The existence of human hippocampal neurogenesis has long been disputed^(1-12) and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD)^(11,13). However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with...

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Increased life expectancy brought about by improved healthcare and lifestyle has heightened the challenge of neurodegenerative disorders like Alzheimer's disease (AD) and other age-related disorders. Neurodegeneration is known to be accompanied by loss of memory, changes in brain morphology, and neuroinflammation, and multiple factors contribute to the progression and pathogenesis of the condition. Of these factors, metabolic dysregulation is known to influence the process, but the precise...

Processing bodies (P-bodies) are conserved ribonucleoprotein granules central to RNA metabolism across eukaryotes. Although the mechanisms underlying their assembly are well understood, the pathways governing their selective turnover remain unclear. Here, we identify the conserved decapping proteins Enhancer of mRNA decapping 4 (EDC4) and decapping protein 1 (DCP1) as a selective autophagy receptor pair responsible for P-body turnover in the model plant Marchantia polymorpha. MpEDC4 engages ATG8...

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The brain continuously integrates rapidly changing visual input across eye movements to maintain stable perception, yet the precise mechanisms underpinning dynamic working memory and how these break down in brain diseases remain unclear. We developed a novel eye-tracking paradigm and computational models to investigate how spatial and colour information are updated across saccades in the human brain. Our findings reveal that saccades selectively impair spatial but not colour memory....

Synaptic Plasticity pertains to the synapse's tendency to adapt fresh information and is a crucial step in the establishment of brain circuits that aid in memory formation. It has become one of the most intensively researched topics in all of neuroscience. Pieces of evidence are accumulating that synaptopathy (altered synaptic plasticity) mechanisms contribute to Alzheimer's disease (AD) and Parkinson's disease (PD). Toxins responsible for synaptopathy and aberrant neurotransmitter (NT) release...

This review synthesizes three decades of evidence regarding the role of cytochrome P450 enzymes (CYPs) in Parkinson's disease (PD), revealing their multifaceted roles beyond traditional pesticide metabolism. While CYP2D6 remains the most studied enzyme due to its association with PD risk in poor metabolizer phenotypes and its dual role in dopamine (DA) synthesis (directly via tyramine hydroxylation and indirectly through precursor demethylation), recent research has highlighted less-studied CYPs...