Alzheimer & Parkinson

Parkinson's disease (PD) is a systemic disorder linked to gut dysbiosis, yet key microbiota-regulated metabolites remain unclear. Here, we observe elevated taurochenodeoxycholic acid (TCDCA) in patients with PD that correlates with disease severity. Reduced bile salt hydrolase (BSH) gene abundance correlates inversely with circulating TCDCA, consistent with altered bile acid deconjugation. Exogenous TCDCA correlates with aggravated motor and gastrointestinal deficits, impaired blood-brain...

Tau phosphorylation is classically associated with neurodegeneration, yet similar phosphorylation patterns emerge during physiological states and acute stress responses. How these overlapping patterns of phosphorylated Tau (pTau) relate to neuronal adaptation and Alzheimer's disease pathology remains unresolved. We synthesize findings from human to rodent and fly brains and from neuronal cell models, across neurodevelopment, sleep, hibernation, cellular stress, and disease. Across these...

Alzheimer's disease (AD) presents distinct extracellular, intracellular and vascular delivery targets, yet brain exposure of candidate therapeutics remains difficult to establish. This narrative review compares hyaluronic acid, chitosan, cyclodextrin, dextran, alginate and pectin systems by construct architecture, route, blood-brain barrier (BBB) evidence, cargo release and biological response. The literature includes covalent drug conjugates, loaded or coated carriers, host-guest complexes and...

Synaptojanin 1 is a brain enriched phosphoinositide phosphatase implicated in endocytosis at the synapse. A mutation (R258Q) that selectively impairs its Sac1 phosphatase domain causes early onset familial Parkinsonism. Neurons of mice with this mutation display synaptic vesicle traffic defects across the brain, but selective dystrophic changes in a subset of dopaminergic axons in the dorsolateral striatum. Using correlative light microscopy-FIB-SEM of mutant mouse striata to visualize in 3D...

A growing body of preclinical research is demonstrating the therapeutic potential of chronic, continuous hypoxia (11% FIO(2)) for rare and common diseases. However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small-molecule, "hypoxia-in-a-pill" combining a hemoglobin affinity enhancer (GBT440) to limit oxygen delivery with a HIF-2α inhibitor (PT2399) to prevent detrimental compensatory erythropoiesis. Although this...

The proteostasis network (PN) safeguards the integrity of proteins by promoting various cellular activities. However, with aging, the PN's competence declines and aggregated proteins accrue within cells. This process underlies the development of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. While the PN functions within cells, proteostasis is regulated across the organism by intertissue communication, which is partially governed by neurons. We previously found that...

Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal...

Despite prolific genomic data from individuals with Alzheimer's disease (AD), translation into treatments has lagged. Here we applied Mendelian randomization to multiple AD genome-wide association studies and functional multiomics datasets to nominate druggable targets, identifying 19 targets for individuals of European ancestry and 7 for African ancestry. This included epoxide hydrolase 2 (EPHX2), for which we identified a protective missense variant (p.Arg287Gln). Experiments in induced...

Microglia are the primary immune cells of the brain, but their role in Parkinson's disease is not fully understood. Chronic microglial activation is toxic to neurons, but in the early stages of pathology, microglia also exert beneficial functions. We used induced pluripotent stem cell (iPSC)-derived coculture models to investigate how human microglia respond to α-synuclein aggregates that form de novo inside human dopaminergic neurons with α-synuclein gene triplication or are triggered by...

Nutritional status and metabolic homeostasis are intricately associated with the inflammatory response. However, the direct mechanistic link between nutrition, metabolism and inflammation remains unclear. Here, we show that the amino acid L-arginine (L-Arg) is a potent endogenous inhibitor of the NLRP3 inflammasome, a central component of the inflammatory signalling pathway. We show that L-Arg binds directly to the Asp31 site of the NLRP3 protein, blocking its interaction with the adaptor ASC...

Cognitive decline in Parkinson's disease (PD), progressing from mild cognitive impairment (PD-MCI) to severe dementia (PD-D), is a debilitating core feature driven by complex neuropathological interactions. While α-synuclein accumulation is the disease's hallmark, co-pathologies involving amyloid-β and tau, alongside chronic neuroinflammation, are critical accelerators of cognitive collapse. This review positions the receptor for advanced glycation end products (RAGE) as a key molecular...

Anti-amyloid antibodies substantially reduce amyloid plaque burden, yet the resulting cognitive benefit remains modest, exposing a limitation in the conventional storage-and-deletion model of memory. We propose that Alzheimer's disease (AD) is better understood as a progressive failure of the dynamic processes that continuously reconstruct memory and bind it to conscious experience, rather than static deletion of stored content following synaptic loss. Amyloid-beta oligomers and mislocalized tau...

Proprioceptive deficits are a core feature of Parkinson's disease (PD), but the neural mechanisms by which transcranial direct current stimulation (tDCS) may augment proprioceptive learning remain unknown. This study investigated whether six sessions of anodal tDCS combined with proprioceptive training modulates EEG‑derived aperiodic activity, Lempel‑Ziv complexity (LZC), and theta clustering in individuals with PD. Twenty‑four participants with mild‑to‑moderate PD were randomly assigned to...

Reduction in brain weight is a hallmark feature of human aging, which is exacerbated in pathologies, such as Alzheimer's disease and other dementias. However, it remains unclear whether a decrease in brain weight with age reflects a vulnerability unique to the human lineage or represents a consequence of an extension of aging processes shared with other primates. To address this question, we examined age-related changes in brain weight across our closest living relatives, the great apes...

Endosomal NHE6 (SLC9A6) and NHE9 (SLC9A9) transporters are essential for maintaining pH homeostasis within endosomes and their dysfunction has been linked to neurological and neurodegenerative disorders. NHE6 and NHE9 are widely considered to function as electroneutral exchangers that couple the export of protons to the import of sodium or potassium ions across cellular membranes, thereby forming the basis of proton leak pathways for internal pH balancing and fine-tuning. Among the 13 identified...

Alzheimer's disease (AD) is associated with amyloid β (Aβ) accumulation, neuronal metabolic dysfunction, and structural degeneration. This study compares the neurotoxic effects of Aβ25-35 and Aβ1-42 in the rat cerebral cortex and hippocampus and evaluates the neuroprotective potential of proline rich peptide 1 (PRP-1). Amyloid peptides were administered bilaterally into the lateral ventricles, followed by intramuscular PRP-1 at 0.1 mg/kg once daily for three weeks, beginning 24 h after amyloid...

Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss...

Parkinsons disease, characterized by the aggregation of alpha-synuclein is a complex neurodegenerative disorder with the fastest global prevalence growth. The identification of shared genes expressed in both blood and brain of Parkinson's disease patients improves the knowledge on peripheral pathophysiology of the disease and facilitates identification of minimally invasive potential biomarkers from these shared genes. Our study intends to identify a shared transcriptomic signature between the...

No therapies ensure long-term survival of dopaminergic neurons in Parkinson's disease. In this context, we propose that early neurodegeneration is an adaptive state of transmissive dormancy, not dysfunction. Upon sensing cellular stress, an inducible transcriptional program restricts cytosolic dopamine and actively silences neurotransmission. This adaptive response precedes neuronal death, reframing early symptoms as programmed dormancy rather than frank degeneration. Thus, reactivation...

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present a temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This...