Alzheimer & Parkinson

Quantification of the absolute microbial abundance in a human stool sample is crucial for a comprehensive understanding of the microbial ecosystem, but this information is lost upon metagenomic sequencing. While several methods exist to measure absolute microbial abundance, they are technically challenging and costly, presenting an opportunity for machine learning. Here, we observe a strong correlation between DNA concentration and the absolute number of 16S ribosomal RNA copies as measured by...

Lipids metabolism is crucial in regulating aging and metabolic diseases. Lipid droplets (LDs) are dynamic, complex organelles responsible for the storage and release of neutral lipids, essential for maintaining lipid homeostasis and energy metabolism. Aging accelerates the accumulation of LDs, functional deterioration, and metabolic disorders, thereby inducing age-related metabolic diseases (ARMDs). This review examines published datasets on the association between LDs and ARMDs, focusing on the...

Antibodies that recognize insoluble antigens, such as amyloid fibrils associated with neurodegenerative disorders, are important for research, diagnostic and therapeutic applications. However, these types of antibodies are difficult to generate, typically require animal immunization and also commonly require humanization in the case of therapeutic applications. Here we report a methodology for generating high-quality, fully human, conformation-specific antibodies against amyloid fibrils using a...

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The most prevalent type of dementia and a progressive neurodegenerative disease, Alzheimer's disease has a major influence on day-to-day functioning due to memory loss, cognitive decline, and behavioral problems. By using synchrosqueezing representations of EEG signals classified by fine-tuned pre-trained convolutional neural networks, this paper presents an EEG-based classification model for Alzheimer's detection. EEG signals are converted into image patterns with time-varying oscillatory...

Alzheimer's Disease (AD) as one of the most prevalent neurodegenerative disorders worldwide, characterized by significant memory and cognitive decline in its later stages, severely impacting daily lives. Consequently, early diagnosis and accurate assessment are crucial for delaying disease progression. In recent years, multimodal imaging has gained widespread adoption in AD diagnosis and research, particularly the combined use of Magnetic Resonance Imaging (MRI) and Positron Emission Tomography...

Mapping enhancers and target genes in disease-related cell types provides critical insights into the functional mechanisms of genome-wide association studies (GWAS) variants. Single-cell multimodal data, which measure gene expression and chromatin accessibility in the same cells, enable the cell-type-specific inference of enhancer-gene pairs. However, this task is challenged by high data sparsity, sequencing depth variation, and the computational burden of analyzing a large number of pairs. We...

Lysosomes maintain an acidic pH of 4.5-5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H^(+) ATPase, proton efflux is mediated by a fast H^(+) leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H^(+) leak through downward flux of...

Recent reports suggest dysregulation of the N6-methyladenosine (m6A) RNA modification may contribute to the pathology of neurodegenerative diseases. Herein, we show the m6A methyltransferase complex including METTL3-the catalytic component of the nuclear-localized complex-is robustly upregulated in human microglia and astrocytes exposed to αSyn(f) and Mn. Subcellular localization studies reveal METTL3 was predominantly cytoplasmic following Mn insult but remained nuclear following αSyn(f)...

Parkinson's disease results from degeneration of dopaminergic neurons in the midbrain, but the underlying mechanisms are unclear. Here, we identify novel crosstalk between depolarization-induced entry of Ca2+ and lysosomal cation release in maintaining dopaminergic neuronal function. The common disease-causing G2019S mutation in LRRK2 selectively exaggerated Ca2+ entry in vitro. Chemical and molecular strategies inhibiting the lysosomal ion channel TPC2 reversed this. Using Drosophila, which...

The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with neurodegenerative diseases, widely regarded to be upregulated in the aging brain. Here we investigated the interaction between aging and TSPO immunomodulatory function in the mouse hippocampus, a region severely affected in Alzheimer's Disease (AD). Surprisingly, we found that TSPO levels were decreased in brain innate immune populations in aging. Aging resulted in a reversal of TSPO knockout...

Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer's disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD...

Amyloid-beta (Aβ) plaque formation in Alzheimer's disease (AD) pathology is morphologically diverse. Understanding the association of polymorphic Aβ pathology with AD pathogenesis and progression is critical in light of emerging Aβ-targeting therapies. In this work, functional amyloid microscopy enhanced by deep learning was integrated with mass spectrometry imaging to delineate polymorphic plaques and to identify their associated Aβ make-up. In both sporadic AD (n = 12) and familial AD (n = 6),...

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N- and C-terminal α-synuclein (α-syn) truncations are prevalent in Parkinson's disease. Effects of the N- and C-terminal residues on α-syn aggregation and fibril propagation are distinct, where the N-terminus dictates fibril structure. Here, the majority of α-syn truncations are assigned by intact mass spectrometry to lysosomal activity. To delineate essential charged residues in fibril formation, we selected an N-terminal truncation (66-140) that is generated solely from soluble α-syn by...

Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of...

Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. Oral administration of ZSS hot water extract...

Aβ is believed to play a significant role in synaptic degeneration observed in Alzheimer's disease and is primarily investigated as a secreted peptide. However, the contribution of intracellular Aβ or other cleavage products of its precursor protein (APP) to synaptic loss remains uncertain. In this study, we conducted a systematic examination of their cell-autonomous impact using a sparse expression system in rat hippocampal slice culture. Here, these proteins/peptides were overexpressed in a...

Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and...

Triplications and certain point mutations in the SNCA gene, encoding alpha-synuclein (α-Syn), cause Parkinson's disease (PD). Here, we demonstrate that the PD-causing A53T α-Syn mutation and elevated α-Syn expression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons and in the CNS of zebrafish and mice. This dysregulation is mediated by activation of ATP-citrate lyase (ACLY), a key enzyme that generates acetyl-CoA in the cytoplasm, via two mechanisms. First, ACLY activity...