Alzheimer & Parkinson

Multi-organ research investigates interconnections among multiple human organ systems, enhancing our understanding of human aging and disease mechanisms. Here we use multi-organ imaging, individual- and summary-level genetics, and proteomics data consolidated via the MULTI Consortium to delineate a brain-heart-eye axis using brain patterns of structural covariance (PSCs), heart imaging-derived phenotypes (IDPs) and eye IDPs. We find that proteome-wide associations of the PSCs and IDPs show...

Biliverdin reductase A (BVRA), the terminal enzyme in heme catabolism, generates the neuroprotective and lipophilic antioxidant bilirubin. Here, we identify a nonenzymatic role for BVRA in redox regulation. Through phylogenetic, genetic, biochemical, and enzymatic assays, we found that BVRA exerts critical nonenzymatic antioxidant activity. Transcriptomic analyses further revealed that BVRA physically and genetically interacts with nuclear factor erythroid-derived factor-like 2 (NRF2), a major...

Excessive endoplasmic reticulum (ER) stress and neuronal apoptosis contribute to neurodegeneration in Parkinson's disease (PD). However, the molecular mechanisms underlying these perturbations and how they are directly regulated remain unclear. B cell receptor-associated protein 31 (BAP31), which is highly expressed in the ER, has been shown to participate mainly in regulating ER stress and apoptosis. Here, our results showed that BAP31 expression was dramatically decreased in PD. Notably,...

Glycine transporter type 1 (GlyT1) regulates extracellular glycine levels and modulates N-methyl-D-aspartate receptor (NMDAR) activity, positioning it as a promising target in excitotoxic and ischemic conditions. While previous studies have shown that GlyT1 inhibition prior to injury confers neuroprotection, its therapeutic potential in a post-ischemic context remains unclear. Here, we investigated the neuroprotective effects of NFPS, a selective GlyT1 inhibitor, administered after the induction...

There is increasing evidence that the pathogenesis of Parkinson's disease (PD) is closely related to mitochondrial dysfunction and iron deposition. Activin A (Act A) is a homodimeric cytokine from the TGF-β superfamily and has neuroprotective effects in various neurological diseases. However, the specific mechanisms by which Act A exerts a neuronal protective effect in PD remain unclear. In this study, we selected lipopolysaccharide (LPS) -induced PD model mice to investigate the mechanism of...

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....

No abstract

No abstract

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...

No abstract

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...