Alzheimer & Parkinson

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The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old...

Vision impairment (VI) and eye diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and cataract have been reported to be associated with cognitive impairment and dementia, however, to date, very little attempt has been made to collate and synthesizes such literature. Therefore, the aim of this umbrella review is to systematically assesses the credibility and certainty of evidence of associations between vision impairment (VI) and eye diseases with...

Selective vulnerability offers a conceptual framework for understanding neurodegenerative disorders such as Parkinson's disease, where specific neuronal types are selectively affected and adjacent ones are spared. However, the applicability of this framework to neurodevelopmental disorders, particularly those characterized by atypical social behaviors, such as autism spectrum disorder, remains uncertain. Here we show that an embryonic disturbance, known to induce social dysfunction in male mice,...

This study investigates the association between cognitive dysfunction and hippocampal volumes in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) using Mendelian randomization. A meta-analysis of 503 healthy controls, 562 MCI patients, and 389 CE patients revealed significant reductions in hippocampal and subregion volumes in MCI and AD compared to controls. While various subregions showed volume reductions, no causal relationship between hippocampal volume and AD was established...

Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility...

Magnetic resonance angiography (MRA) is pivotal for diagnosing panvascular diseases. However, single-modality MRA falls short in diagnosing diverse vascular abnormalities. Thus, contrast agents combining T(1) and T(2) effects are sought for multiparameter MRA with clinical promise, yet achieving a balance in T(1) and T(2) contrast enhancement effects remains a scientific challenge. Herein, we developed a hypersensitive multiparameter MRA strategy using dual-modality NaGdF(4) nanoparticles....

Agency fines Cassava Sciences $40 million for touting flawed research on simufilam.

Alzheimer's disease (AD) remains a pressing global health concern, necessitating comprehensive investigations into its underlying molecular mechanisms. While the late-stage pathophysiology of this disease is well understood, it is crucial to examine the role of amyloid beta oligomers (Aβo), which form in the brain during the early stages of disease development. These toxic oligomers could affect neuronal viability and generate oxidative stress in the brain. In this study, we exposed SHSY-5Y...

While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer's disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ) peptide is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans, we discovered that the CTSB CPR-6 promotes Aβ...

Traumatic brain injury (TBI) is a leading cause of long-term disability across the world. Evidence for the usefulness of imaging and fluid biomarkers to predict outcomes and screen for the need to monitor complications in the acute stage is steadily increasing. Still, many people experience symptoms such as fatigue and cognitive and motor dysfunction in the chronic phase of TBI, where objective assessments for brain injury are lacking. Consensus criteria for traumatic encephalopathy syndrome, a...

Emerging evidence links type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), with brain insulin resistance (BIR) as a key factor. In a recent study, Lanzillotta et al. reveal that reduced biliverdin reductase-A (BVR-A) impairs glycogen synthase kinase 3β (GSK3β) phosphorylation, causing mitochondrial dysfunction and exacerbating brain insulin resistance in the progression of both T2DM and AD.

Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially...

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Oxidative stress has long been implicated in Parkinson's disease (PD) pathogenesis, although the sources and regulation of reactive oxygen species (ROS) production are poorly defined. Pathogenic mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are associated with increased kinase activity and a greater risk of PD. The substrates and downstream consequences of elevated LRRK2 kinase activity are still being elucidated, but overexpression of mutant LRRK2 has been associated with...

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and cognitive decline, the latter of which is thought to be driven by soluble oligomeric amyloid-β (oAβ). The dysregulation of G protein-gated inwardly rectifying K^(+) (GIRK; also known as Kir3) channels has been implicated in rodent models of AD. Here, seeking mechanistic insights, we uncovered a sex-dependent facet of GIRK-dependent signaling in AD-related amyloid pathophysiology. Synthetic...

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2^(R47H) (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4...

Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for...

The basal ganglia are subcortical brain structures involved in motor control, cognition, and emotion regulation. We conducted univariate and multivariate genome-wide association analyses (GWAS) to explore the genetic architecture of basal ganglia volumes using brain scans obtained from 34,794 Europeans with replication in 4,808 white and generalization in 5,220 non-white Europeans. Our multivariate GWAS identified 72 genetic loci associated with basal ganglia volumes with a replication rate of...