Alzheimer & Parkinson

Levodopa-induced dyskinesia (LID) is a complication that occurs in many patients with Parkinson's disease. (-)-OSU6162 is a clinically tolerable dopamine stabilizer with affinity for both dopaminergic D(2) receptors and serotonergic 5-HT(2A) receptors which has been shown to counteract LID in non-human primates. To investigate whether (-)-OSU6162 can dampen levodopa-induced abnormal involuntary movements in the unilateral 6-OHDA rat model of Parkinson's disease without impairing levodopa-induced...

MicroRNAs (miRNAs) have emerged as key regulators of neuroplasticity, influencing essential processes such as neurogenesis, synaptogenesis, and neuroinflammatory responses. This review provides a comprehensive overview of the general roles of miRNAs in neuroplasticity and synthesizes recent insights from both preclinical and clinical studies, including transcriptomic analyses and miRNA profiling, to elucidate the molecular mechanisms by which these miRNAs modulate neuronal function. We have...

Nucleoside Reverse Transcriptase Inhibitors (NRTIs), widely used to treat HIV and hepatitis B, have recently been shown to possess anti-inflammatory properties by inhibiting inflammasome activation. Epidemiological studies have revealed a significantly reduced incidence of age-related diseases, such as Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), among patients chronically treated with NRTIs, but not with other classes of antiretroviral drugs. In this short review, we explore...

Alzheimer's disease (AD) and AD-related dementias (AD/ADRD) have a substantial genetic basis, with APOE4 homozygotes increasingly recognized as a distinct genetic subtype. To identify genotype-specific metabolic pathways and modifiable risk factors, we integrated genetic, plasma metabolomic and dietary data from 4,215 women and 1,490 men in prospective cohorts. Here we show that the associations of 57 metabolites with dementia risk varied by APOE4 genotype or other AD/ADRD risk variants. For...

The spreading of MAPT/Tau pathology is closely associated with the progression of neurodegeneration and cognitive decline in Alzheimer disease and other tauopathies. A key event in this process is the rupture of endolysosomal vesicles following the intercellular transfer of MAPT/Tau aggregates, releasing the transferred MAPT/Tau species into the cytosol where they can promote the aggregation of endogenous MAPT/Tau. However, understanding of the cellular pathways involved in this process remains...

ATP13A2 is an endolysosomal polyamine transporter mutated in several neurodegenerative conditions involving lysosomal defects, including Parkinson's disease (PD). While polyamines are polybasic and polycationic molecules that play pleiotropic cellular roles, their specific impact on lysosomal health is unknown. Here, we demonstrate lysosomal polyamine accumulation in ATP13A2 knockout (KO) cell lines and human induced pluripotent stem cell (iPSC)-derived neurons. Primary polyamine storage caused...

A blood biomarker-based staging system for Alzheimer's disease (AD) could improve the diagnosis, prognosis and identification of individuals most likely to benefit from specific therapies. Here, using targeted mass spectrometry, we measured six phosphorylated and six nonphosphorylated tau peptides in plasma from two independent cohorts: BioFINDER-2 and TRIAD (n = 689). We also analyzed the ratios of phosphorylated to nonphosphorylated peptides. Our results revealed that specific tau species...

Increasing evidence strongly links neuroinflammation to Alzheimer's disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation. By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates,...

Age-related neurodegeneration is one of the primary causes associated with the pathogenesis of Alzheimer's disease (AD). Currently, there are 5.8 million cases of AD worldwide. With the advancement in technology, the paradigm of treating the disease has shifted from one treatment or diagnosis to simultaneously diagnosing as well as treating the disease. Excellent efforts have been made by the scientists towards the development of nanotheranostics. Among them, quantum dots (QDs) have shown...

The complicated pathogenesis of Alzheimer's disease (AD) is characterized by the accumulation of neurofibrillary tangles and senile plaques, primarily composed of tau and amyloid-β (Aβ) aggregates, respectively. While substantial efforts have focused on unraveling the individual roles of tau and Aβ in AD development, the intricate interplay between these components remains elusive. Here we report how the microtubule-binding repeats of tau engage with Aβ in a distinct manner. Crucially, this...

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Functional gene programs play a wide range of roles in health and disease by orchestrating transcriptional coregulation to govern cell identity. Understanding these intricate gene programs is essential for unraveling the complexities of biological systems; however, deciphering them remains a significant challenge. Recent advancements in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) technologies have empowered the comprehensive characterization of gene programs at both...

Proteomic profiling of Alzheimer disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with amyloid-β (Aβ) from the early disease stage but their roles in disease progression are not fully understood. Here, we present that MDK attenuates Aβ assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both Aβ40 and Aβ42 peptides according to thioflavin T...

Presynaptic terminals can be located far from the neuronal cell body and are thought to independently regulate protein and organelle turnover. Autophagy is a critical process for maintaining proteostasis, and its synaptic dysregulation is associated with neurodegenerative diseases. In this work, we report a soma-centered mechanism that regulates autophagy-controlled protein turnover at distant presynaptic terminals in Drosophila. We show that a central component of this system is Rab39, whose...

Parkinson's disease (PD), a progressive neurodegenerative disorder, presents complex motor symptoms and lacks effective disease-modifying treatments. Here we show that integrating artificial intelligence (AI) with optogenetic intervention, termed optoRET, modulating c-RET (REarranged during Transfection) signalling, enables task-independent behavioural assessments and therapeutic benefits in freely moving male AAV-hA53T mice. Utilising a 3D pose estimation technique, we developed tree-based AI...

Because the central nervous system (CNS) is an immune-privileged organ, it requires different immunosuppression strategies for cell therapies using induced pluripotent stem cells (iPSCs) compared with ones for organ transplantations. We recently conducted the first in-human clinical trial of a cell therapy for Parkinson's disease using allogeneic iPSCs (jRCT number: jRCT2090220384). All patients were transplanted with dopaminergic neural progenitors differentiated from iPSCs (iPSC-DANs), which...

Perioperative neurocognitive disorder (PND) is a significant neurological complication in aging perioperativepatients, seriously impacting their postoperative recovery and cognition as well as quality of life. The occurrence of PND is closely related to various factors, including neuroinflammation and oxidative stress, while the exact mechanism is still unknown. Mitophagy is a specialized form of autophagy and maintains cellular homeostasis by selectively degrading damaged and dysfunctional...

Light can serve as a tunable trigger for neurobioengineering technologies, enabling probing, control, and enhancement of brain function with unmatched spatiotemporal precision. Yet, these technologies often require genetic or structural alterations of neurons, disrupting their natural activity. Here, we introduce the Graphene-Mediated Optical Stimulation (GraMOS) platform, which leverages graphene's optoelectronic properties and its ability to efficiently convert light into electricity. Using...

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...