Alzheimer & Parkinson

Microtubules are dynamic cytoskeletal polymers whose lattice architecture regulates force generation, nucleotide hydrolysis, and recognition by motor proteins and microtubule-associated proteins (MAPs). Microtubule-stabilizing agents (MSAs), including taxanes and laulimalide/peloruside-site ligands, suppress depolymerization by binding to defined lattice sites, yet stabilization is not structurally neutral. How ligand chemistry reshapes lattice organization and function remains unresolved. Here,...

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Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline. Although AD is primarily an age-related brain pathology, increasing evidence indicates dysfunction in peripheral nerves and skeletal muscle may manifest early in the disease progression. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood. Sciatic nerves from 5xFAD and wild-type (WT) mice were...

Quantitative insights into brain metabolism are essential for advancing our understanding of the energy dynamics in the brain. Here, we present a nanowatt-resolution biocalorimeter capable of real-time metabolic heat output measurements of individual, live Drosophila melanogaster brains. Using this platform, we show that female brains, across multiple genotypes, exhibit a significantly higher metabolic rate (∼10%-15%) than male brains at a young age (<10 days old) and follow distinct metabolic...

Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) that has been related to abnormal functional connectivity across motor, cognitive, and limbic networks. However, it remains unclear how directional (i.e., effective) connectivity between various networks is altered by an actual FOG-related motor imagery task. Twenty-four individuals with PD (11 freezers and 13 non-freezers) and 15 healthy controls underwent functional MRI. Participants performed a motor imagery task...

Parkinson's disease leads to a spectrum of locomotor deficits that vary in severity with the nature of daily activities and the fluctuating physiology of patients. Many of these deficits remain inadequately addressed by existing deep brain stimulation therapies that rely on activity-agnostic parameters optimized for cardinal motor symptoms. By contrast, therapies embedding activity-specific parameters have the potential to better address the entire range of symptoms. Here we expose physiological...

A randomized crossover study of five patients with Parkinson's disease (PD) demonstrates that gait-synchronized adaptive deep brain stimulation is feasible and safe, and reduces falls compared with continuous stimulation. Gait dysfunction in PD is a major source of disability and is often insufficiently treated by continuous deep brain stimulation (cDBS). Although adaptive DBS (aDBS) has shown efficacy for other motor symptoms using β-based, state-driven neural signals, gait is a dynamic,...

Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20-25% of individuals exhibited accelerated aging in a single cell type and 1-3% in 10 or more...

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Mitochondrial endonuclease G (EndoG) is involved in several important cellular processes and has been implicated in multiple diseases. Accordingly, molecules modulating EndoG activity may have high therapeutic potentials. Searching for compounds affecting paternal mitochondrial elimination (PME) in Caenorhabditis elegans, we have identified resveratrol (RSV), a well-known natural compound, as a PME inhibitor. Interestingly, RSV exists as a mixture of trans- and cis-isomers, which interconvert...

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Amyloid-β (Aβ) accumulation in the brain is a defining pathological feature of Alzheimer's disease (AD). Cerebral Aβ burden is regulated not only by central production and degradation but also by its transport and clearance in the peripheral circulation. Blood-borne Aβ carriers provide a potential peripheral route for reducing brain Aβ levels by strengthening the brain-to-blood concentration gradient, representing a therapeutic strategy that does not require direct penetration of the blood-brain...

Neurodegenerative diseases share common pathophysiological mechanisms, including chronic neuroinflammation, glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, and disruptions in synaptic and lipid homeostasis. In this context, the endocannabinoid system has emerged as a key modulator of neuroimmune communication and neuronal survival. Within this system, Monoacylglycerol Lipase (MAGL) plays a central role by regulating the levels of the endocannabinoid...

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A growing body of evidence supports the contribution of the long-lasting adaptive immune system in Parkinson's disease (PD). We showed that the PD-associated protein PINK1 negatively regulates the presentation of mitochondrial antigens (MitAP) on MHC-I molecules. In vivo evidence indicated that MitAP activation in mice, in the absence of PINK1, led to cytotoxic CD8^(+) T cell stimulation and severe motor impairments, reversible by L-DOPA. We show here that following TLR4 activation, MitAP is...

Amyloid precursor protein (APP) is widely known for its role in Alzheimer's disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological functions remain incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell...

Alzheimer's disease (AD), characterized by progressive cognitive decline, represents a major public health challenge in aging societies. Since the proposal of the amyloid cascade hypothesis, Aβ-targeted therapeutic strategies have dominated this field for over three decades. Although recent anti-Aβ antibodies have shown modest promise, their limited clinical benefits coupled with safety concerns underscore the necessity of re-evaluating the pathological mechanisms underlying AD. Cerebral...

The cerebellum contains most of the brain's neurons and supports many functions, yet how it changes with age remains unclear. Here we used three brain imaging studies spanning 47,000 adults and examined how different parts of the cerebellum age and their relation to cognition. We characterized cerebellar aging using volumetry and the T1-weighted/T2-weighted ratio, and corroborated these findings with quantitative magnetic resonance imaging in an independent sample. We show a spatially...

Restoring striatal dopamine synthesis is a promising gene therapy strategy for Parkinson's disease. Previous adeno-associated virus-mediated aromatic L-amino acid decarboxylase (AADC) monotherapies remain dependent on exogenous levodopa, whereas multigene delivery is constrained by strict adeno-associated virus packaging limits. A 'dual approach' targeting the two rate-limiting enzymes, tyrosine hydroxylase (TH) and AADC, offers the potential for autonomous dopamine synthesis. We report the...