Alzheimer & Parkinson

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with mitochondrial dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation. The silent information regulator 2 (Sir2) family of proteins, known as sirtuins (SIRT1 - SIRT7), is nicotinamide adenine dinucleotide (NAD^(+))-dependent histone deacetylases that regulate important signal transduction pathways in both prokaryotes and eukaryotes. An increasing number of studies revealed that...

Aging represents a major risk for human neurodegenerative disorders, such as dementia and Alzheimer's disease, and is associated with a functional decline in neurons and impaired synaptic plasticity, leading to a gradual decline in memory. Previous research has identified molecular and functional changes associated with aging through transcriptomic studies and neuronal excitability measurements, while the role of chromatin-level regulation in vulnerability to aging-related diseases is not well...

The molecular mechanisms underlying the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, remain poorly understood. Proteomics offers a crucial approach to elucidating AD pathogenesis, as alterations in protein expression are more directly linked to phenotypic outcomes than changes at the genetic or transcriptomic level. In this study, we develop multiscale proteomic network models for AD by integrating large-scale matched proteomic and genetic data from brain regions...

Preclinical evidence suggests positive symptomatic and neuroprotective effects of hypoxic conditioning in Parkinson's disease (PD). This study (NCT05214287) investigated the safety, feasibility, short-term symptomatic and downstream effects of hypoxic conditioning in individuals with PD. 20 individuals with PD (mean age 62, 10 women, Hoehn-Yahr 1.5-3) completed randomized controlled double-blinded multiple N-of-1 trials. Each participant underwent five different 45-minute hypoxia interventions...

GBA is the major risk gene for Parkinson's disease (PD) and dementia with Lewy bodies (DLB), two common α-synucleinopathies with cognitive deficits. Here we investigate the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice show cognitive decline but lack PD-like motor deficits or α-synuclein pathology. Conversely, SNCA tg mice display age-related motor deficits, without cognitive abnormalities....

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Alzheimer's disease involves a drastic departure from the cognitive, functional, and behavioural trajectory of normal ageing, and is both a dreaded and highly prevalent cause of disability to individuals, and a leading source of health and social care expenditure for society. Before the advent of biomarkers, post-mortem examination was the only method available to establish a definitive diagnosis. In this first paper of the Series, we review state-of-the-art diagnostic practices and the typical...

Over the last three decades, the evidence on how to best treat the cognitive and non-cognitive symptoms of patients with Alzheimer's disease has increased. Although these pharmacological and non-pharmacological strategies have significantly improved health outcomes for patients with Alzheimer's disease, many lack stringent evidence of efficacy. In this second paper of the Series, we provide practical and realistic advice on how to prioritise pharmacological and non-pharmacological strategies to...

For the first time, reductions in cerebral β-amyloid pathology load and rate of cognitive and functional decline have been achieved in Alzheimer's disease, through pharmacological intervention in randomised controlled trials. However, the results from phase 3 randomised controlled trials of anti-β amyloid monoclonal antibodies are interpreted in different ways, with some experts supporting a clinically meaningful disease-modifying effect, and others judging insufficient benefit-to-risk ratio and...

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Immune mechanisms contribute to the neuropathology of Alzheimer's disease (AD) but the role of adaptive immune cells is unclear. Here we show that the brain CD8^(+) T cell compartment is dysregulated in AD patients and in the 3xTg-AD mouse model, accumulating activated CD103^(-) tissue-resident memory T cells that produce large amounts of granzyme K (GrK). These CD103^(-)CD8^(+) T cells originate from the circulation and migrate into the brain using LFA-1 integrin. Ablation of brain...

Brain-computer interface research can inspire closed-loop neuromodulation therapies, promising spatiotemporal precision for the treatment of brain disorders. Decoding dynamic patient states from brain signals with machine learning is required to leverage this precision, but a standardized framework for invasive brain signal decoding from neural implants does not exist. Here we develop a platform that integrates brain signal decoding with magnetic resonance imaging connectomics and demonstrate...

Lysosomes are dynamic organelles that remodel their membrane in response to stimuli. We previously uncovered a process we term LYsosomal Tubulation/sorting driven by LRRK2 (LYTL), wherein damaged lysosomes generate tubules sorted into vesicles. LYTL is orchestrated by the Parkinson's disease kinase LRRK2 that recruits the motor adaptor protein and RHD family member JIP4 to lysosomes. JIP4 enhances LYTL tubule extension toward the plus-end of microtubules. To identify new players involved in...

Somatodendritic missorting of the axonal microtubule-associated protein Tau is an early hallmark of Alzheimer's disease (AD) and other tauopathies. Tau missorting causes synaptic loss and neuronal dysfunction, but the mechanisms underlying both normal axonal sorting and pathological missorting remain unclear. The six human brain Tau isoforms show different axodendritic distribution, but the Tau domains governing intracellular sorting and essential interactors are unknown. Here, we aimed to...

Parkinson's disease (PD) is characterized by extensive motor and non-motor dysfunction, including gait disturbance, which is difficult to treat effectively. This study explores the therapeutic potential of targeting the A13 region, a heterogeneous region of the medial zona incerta (mZI) containing dopaminergic, GABAergic, and glutamatergic neurons that has shown relative preservation in PD models. The A13 is identified to project to the mesencephalic locomotor region, with a subpopulation of...

Hesperidin is a flavonoid renowned for its significant pharmacological effects and promising therapeutic potential. It is ubiquitous in the plant kingdom and is a common constituent of our daily diets, primarily in fruits and vegetables. Several cellular and animal models have been developed to evaluate the underlying neuropharmacological mechanisms of hesperidin. Additionally, clinical evidence has also confirmed itsneuroprotectivefunction. Hesperidin exerts neuroprotective properties by...

Parkinson's disease (PD) is a neurodegenerative disorder with a worldwide prevalence of around 9.4 million that is expected to double by 2040. It's extended prodromal phase allows irreversible neuronal loss to occur before manifestation of symptoms. Current diagnostic approaches, primarily based on clinical assessment and neuroimaging, are often delayed and lack sensitivity in the early stages, highlighting the need for an early, conclusive, and minimally invasive test. This review focuses on...

Lipid alterations in the brain have been implicated in many neurodegenerative diseases. To facilitate comparative lipidomic research across brain diseases, we establish a data common named the Neurolipid Atlas that we prepopulated with isogenic induced pluripotent stem cell (iPS cell)-derived lipidomics data for different brain diseases. Additionally, the resource contains lipidomics data of human and mouse brain tissue. Leveraging multiple datasets, we demonstrate that iPS cell-derived neurons,...

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