Alzheimer & Parkinson

Mitochondrial biogenesis requires the import of ∼1,000-1,500 nuclear-encoded proteins across the Translocase of Outer Membrane (TOM) and the Translocase of Inner Membrane (TIM) 22 or 23 complexes. Protein import defects cannot only impair mitochondrial respiration but also cause mitochondrial Precursor Overaccumulation Stress (mPOS) in the cytosol. Recent studies have shown that specific mutations in the nuclear-encoded Adenine Nucleotide Translocase 1 (ANT1) cause musculoskeletal and...

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder, defined pathologically by the accumulation of Aβ plaques and Tau neurofibrillary tangles, accompanied by widespread metabolic dysregulation. Recently, "metabolic reprogramming (MetR)", referring to the dynamic adaptation of cellular metabolic networks in response to environmental or functional demands, has emerged as a novel conceptual perspective for understanding AD. In the context of AD, the dysregulation of MetR is...

Cystathionine γ-lyase (CSE), the enzyme responsible for neuronal cysteine and hydrogen sulfide production, is dysregulated in aging and neurodegenerative diseases including Alzheimer's disease and Huntington's disease, both marked by cognitive decline in addition to motor deficits. To determine whether CSE loss directly causes cognitive decline, we genetically ablated CSE in mice. This loss was sufficient to induce oxidative damage, compromise blood-brain barrier integrity, impair neurogenesis...

A marked evolution in Alzheimer's disease (AD) therapy research is ongoing. In this perspective, we highlight emerging outcomes of tau-targeting approaches with disease-modifying potential evidenced by PET-based slowing of tau accumulation and early signs of cognitive benefit. We outline how decades of iterative amyloid β (Aβ)-trial refinement leading to the recent successes of approved anti-Aβ therapies have set the stage for accelerated optimization of next-generation trials. We summarize key...

Emerging neuroimaging evidence has propelled the formulation of the hypothesis that freezing of gait (FOG) in Parkinson's disease (PD) arises from dysfunction within the locomotor network. However, to date, there has been a lack of functional connectivity analyses targeting the hyperdirect pathway (HDP) to explore this hypothesis. In this study, we investigate impaired communication within the HDP neural circuitry in FOG patients. Fifty-nine PD patients (33 PD-nFOG and 26 PD-FOG) and thirty...

CONCLUSION: In conclusion, this study provides evidence that Apremilast may exert protective effects against Aβ-induced cytotoxicity in BV2 and HT-22 cells by modulating the PI3K/Akt signaling pathway. However, further validation of its dosage and efficacy in vivo is required.

α-Synuclein (α-syn) fibrils accumulate in Parkinson's disease, spreading between cells to template misfolding and drive neurodegeneration. α-Syn fibril entry into healthy neurons is a key step. Here, we comprehensively assessed the membrane proteome for α-syn fibril binding. We identified mGluR4 and NPDC1 as nigral surface proteins binding and internalizing α-syn fibrils. While striatal α-syn fibril injection led to nigral dopamine neuron loss in wild type mice, deletion of either Grm4 or Npdc1...

Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD^(+)) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full...

Genetic variations in MS4A4A and MS4A6ATriggering receptor expressed on myeloid cells 2 (TREM2) are linked to the regulation of cerebrospinal-fluid-soluble TREM2 levels and are associated with Alzheimer's disease (AD) risk and progression. By modulating MS4A4A using knockout, overexpression, and degrading antibodies in macrophages, microglia, non-human primates (NHPs), and a mouse model of amyloid pathology, we provide evidence that MS4A4A and MS4A6A are negative regulators of both the...

Stem cell-derived extracellular vesicles (EVs) show promise as a therapeutic approach for neurodegenerative diseases, particularly Alzheimer's Disease (AD), where traditional regenerative interventions have achieved limited success. Our previous research demonstrated the neuroprotective benefits of human neural stem cell (hNSC)-derived EVs in 2- and 6-month-old AD mice (5xFAD) that exibited improved cognitive function and reduced AD-related neuropathology. This study aimed to compare the...

Brain capillaries are sensors of neural activity. When a brain region is active, capillary endothelial cells (ECs) sense neuron-derived mediators and elicit a local increase in blood flow (functional hyperemia) to support the rise in metabolic needs. This hyperemic response involves a rapid electrical component and a slower chemical component that involves Gαq PCR (G(q)PCR) activation by agonists released from neurons. The intravascular forces associated with hyperemia engage mechanosensitive...

Antibody-drug conjugates (ADCs) are emerging as a targeted therapeutic strategy for Alzheimer's disease (AD), offering precise delivery of disease modifying agents with reduced systemic toxicity. By linking monoclonal antibodies to small-molecule payloads, ADCs hold promise in overcoming key challenges in AD treatment, including poor blood-brain barrier (BBB) penetration and off-target effects. This review provides a critical synthesis of ADC strategies in neurodegeneration, with emphasis on...

Olfactory impairment is an early symptom of Alzheimer's disease (AD). However, currently used olfactory task-based functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), and electroencephalogram features are not powerful enough to detect the impairment. To address this issue, we propose an explainable Artificial Intelligence (XAI) framework that comprises discriminant analysis/naive Bayes/thresholding classifiers driven by the sample entropy (SE) of...

Neuronal hyperexcitability-defined as increased likelihood of action potential firing in response to stimuli-has emerged as a key pathophysiological feature in both normal aging and Alzheimer's disease (AD). This review synthesizes current evidence across species and models, evaluating the prevalence, mechanisms, and consequences of heightened excitability at the cellular and network levels. We examine electrophysiological and imaging-based indicators of hyperexcitability, including enhanced...

Aducanumab, a human IgG1 antibody with plaque-clearing effects and modest clinical benefit, binds selectively to aggregated Aβ via the N-terminal region. Yet, the molecular details of how the antibody engages Aβ(1-42) fibrils remain unresolved. Using magic-angle spinning NMR, we show that binding of aducanumab preserves the overall architecture of the Aβ(1-42) fibril core while inducing significant structural and dynamic perturbations in the N-terminal region. Antibody binding markedly reduces...

Scopolamine, a muscarinic receptor antagonist, is widely utilized to pharmacologically model Alzheimer's disease (AD) due to its ability to mimic cholinergic deficits and induce memory impairments. Despite its common use in investigating behavioral and cognitive impairments in memory deficit animal models, the longitudinal brain-wide electrophysiological alterations associated with scopolamine administration remain largely unexplored. This study integrated electrophysiological and behavioral...

Aging increases the risk of neurodegeneration, cognitive decline, and Alzheimer's disease (AD). We report that plasma concentrations of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and neurofilament light (NfL) become exponentially higher from ages 2 to 85 in cross-sectional samples, serving as neuronal death/damage biomarkers across the lifespan. UCH-L1 concentrations rise faster in females, who exhibit increased AD risk. Glial fibrillary acidic protein (GFAP) concentrations increase...

Neuroimaging studies have highlighted both hyperconnectivity and hypoconnectivity across the Alzheimer's disease (AD) continuum, alongside task-induced activity changes. These alterations may reflect compensatory mechanisms or network breakdowns. While connectivity-based measures are not yet established as clinical biomarkers, they hold promises for evaluating therapeutic efficacy and informing the design of targeted interventions. Based on these insights, this review explores the potential of...

Alzheimer's disease (AD) is the most chronic neurodegenerative disease. The pathological hallmark of AD includes the accumulation of amyloid-beta plaques (Aβ), oxidative stress as well as chronic inflammatory reactions. Current treatments, such as acetylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, and recently approved monoclonal antibodies, offer symptomatic relief or slightly slow down progression. However, they too are constrained by high cost, side effects and...

During deep co-evolution of viruses and host cells, viruses have selected specific host cellular proteins redirected from physiological functions to viral needs, thereby disturbing cellular proteostasis and increasing the risk of triggering protein misfolding diseases (PMDs). Identifying virus-specific, repurposed host proteins also allows the study of fundamental cellular events in "sporadic" PMDs, independent of the virus. Here, we identify a small molecule with very strong activity against...