Alzheimer & Parkinson

Understanding and treating inflammation has proven a formidable challenge. The initiator and central motor of inflammation, the protein NLRP3, is an innate immune sentinel and nonspecific sensor of cellular perturbation. A wide array of inflammatory triggers prompts the formation of an NLRP3 'inflammasome' complex, leading to inflammatory interleukin-1 family cytokine release and pyroptotic cell death. Since gain-of-function mutations in NLRP3 were demonstrated to cause a rare autoinflammatory...

Beyond their classical roles in hemostasis and coagulation, accumulating evidence highlights platelets as multifaceted regulators within the nervous system. Research has revealed that platelet-derived factors promote blood-brain barrier (BBB) maturation and angiogenesis via neurochemical pathways. At the same time, platelet-rich plasma (PRP) facilitates neural regeneration by mitigating the neurotoxicity of amyloid-beta (Aβ) and activating the PI3k/Akt signaling pathway. Platelets also modulate...

Mitochondrial dysfunction and accumulation of α-synuclein aggregates are hallmarks of the neurodegenerative Parkinson's disease and may be interconnected. To investigate the interplay between α-synuclein and brain mitochondria at near atomic structural level, we apply NMR and identify α-synuclein protein interactors using limited proteolysis-coupled mass spectrometry (LiP-MS). Several of the proteins identified are related to ATP synthesis and homeostasis and include subunits of ATP synthase and...

Parkinson's Disease (PD) is a progressive neurodegenerative disorder marked by motor impairments such as tremors, rigidity, and bradykinesia. Regular physical activity plays a key role in managing these symptoms, yet the COVID-19 pandemic imposed social isolation measures that significantly curtailed physical activity, potentially accelerating motor decline. This systematic review aimed to synthesize evidence on the impact of pandemic-related social isolation on motor symptom deterioration in...

Neurodegeneration is a hallmark of various neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), stroke, and neurotropic viral infections. Although the precise etiology remains unclear, multiple pathological mechanisms contribute to disease progression, including mitochondrial dysfunction, protein aggregation, calcium excitotoxicity, endoplasmic reticulum (ER) stress, oxidative stress, immune system activation, and neuroinflammation. Among these, the immune...

Malawi is undergoing demographic shifts in age that will inevitably increase the prevalence of neurodegenerative disorders like Parkinson s disease (PD). However, there is a knowledge gap about the clinical profiles of patients with PD in the country. This cross-sectional study analyzed the clinical characteristics of thirty-two patients with PD at Queen Elizabeth Central Hospital in Blantyre Malawi using a structured questionnaire and the Movement Disorder Society Unified PD Rating Scale. The...

The protein α-synuclein, encoded by SNCA, accumulates in Parkinson's disease (PD) and other synucleinopathies for reasons that remain unclear. Here, we investigated whether SNCA is regulated in vivo by the RNA-binding protein PUM1. We establish that PUM1 binds to SNCA's 3' UTR in mouse and human cells. In induced neurons from patients with SNCA locus triplication, PUM1 mRNA levels are lower than in healthy controls, but increasing PUM1 normalizes both SNCA mRNA and α-synuclein protein levels,...

Alzheimer's disease and related dementias (AD/ADRDs) pose a significant global public health challenge. To effectively implement personalized therapeutic interventions on a global scale, it is essential to identify disease-causing, risk, and resilience factors across diverse ancestral backgrounds. This study leveraged biobank-scale data to conduct a large multi-ancestry whole-genome sequencing characterization of AD/ADRDs. We thoroughly explored the role of protein-coding and splicing variants...

The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent...

Late-onset depression (LOD) is closely linked to Alzheimer's disease (AD), marked by shared biological pathways and common risk factors. The neurobiological alterations associated with depression, particularly the dysregulation of amyloid-β (Aβ), play a critical role in the acceleration of disease progression. In individuals suffering from LOD, Aβ peptides - specifically Aβ40 and Aβ42 - exhibit distinct profiles in plasma, cerebrospinal fluid (CSF), and brain tissue, highlighting the substantial...

The "Christchurch" protective variant in the APOE gene has recently been identified, but its mechanisms of action remain unknown. In this issue of Immunity, Naguib and Lopez-Lee et al. provide evidence for the APOE-Christchurch variant suppressing microglial cGAS-STING responses and increasing clearance of pathological tau aggregates in mouse models of Alzheimer's disease.

Hyposmia, a common non-motor symptom in Parkinson's disease (PD) linked to reduced odor sensitivity, is associated with brain structural and functional changes, but dynamic brain activity and altered regional information exchange remain underexplored, limiting insight into underlying brain states. We selected 15 PD patients with severe hyposmia (PD-SH), 15 PD patients with normal cognition (PD-CN), and 15 healthy controls (HC). Using functional MRI, we assessed the brain's spatiotemporal...

False positive claims of differentially expressed genes (DEGs) in scRNA-seq studies are of substantial concern. We found that DEGs from individual Parkinson's (PD), Huntington's (HD), and COVID-19 datasets had moderate predictive power for case-control status of other datasets, but DEGs from Alzheimer's (AD) and Schizophrenia (SCZ) datasets had poor predictive power. We developed a non-parametric meta-analysis method, SumRank, based on reproducibility of relative differential expression ranks...

The meninges serve as a critical interface between the peripheral immune system and the central nervous system, playing a crucial role in maintaining parenchymal homeostasis. Neurodegenerative disorders, such as amyloidosis and tauopathies, are marked by the accumulation of extracellular neurotoxic amyloid-β (Aβ) plaques and intracellular tau tangles, respectively, leading to neuronal cell death and cognitive decline. The role of the adaptive immune response in these pathologies remains under...

CONCLUSIONS: Our study highlights the complex relationship between genetic legacies and modern diseases, emphasizing the need for gender-sensitive healthcare strategies that consider the unique connections between female reproductive health and aging.

Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (G(s)) could rapidly promote the activity of the organelle and possibly...

Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins - amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) - are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are...

Extracellular release and uptake of pathogenic forms of the microtubule-associated protein tau contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease. Defining the cellular mechanisms and pathways for tau entry to human neurons is essential to understanding tauopathy pathogenesis and enabling the rational design of disease-modifying therapeutics. Here, whole-genome, loss-of-function CRISPR screens in human iPSC-derived excitatory neurons, the major...

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction, with spatial memory impairments among the earliest detectable deficits. The dentate gyrus (DG), a critical region for spatial discrimination, exhibits functional alterations in patients with AD. Adult-born granule cells (abGCs) with higher intrinsic excitability are involved in DG-dependent spatial memory. However, it remains unclear the changes in intrinsic excitability of abGCs and...