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Alzheimer & Parkinson

HER-096 is a CDNF-derived brain-penetrating peptidomimetic that protects dopaminergic neurons in a mouse synucleinopathy model of Parkinson's disease

1 day 4 hours ago
Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotropic factor that modulates unfolded protein response (UPR) pathway signaling and alleviates endoplasmic reticulum (ER) stress providing cytoprotective effects in different models of neurodegenerative disorders. Here, we developed a brain-penetrating peptidomimetic compound based on human CDNF. This compound called HER-096 shows similar potency and mechanism of action as CDNF, and promotes dopamine neuron survival, reduces...
Natalia Kulesskaya

Heat Shock Protein 90 in Parkinson's disease: Profile of a serial killer

1 day 4 hours ago
Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by abnormal α-synuclein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, as well as progressive death of dopaminergic neurons in the substantia nigra. Molecular chaperones play a role in stabilizing proteins and helping them achieve their proper structure. Previous studies have shown that overexpression of heat shock protein 90 (HSP90) can lead to the death of dopaminergic neurons...
Heba M Mansour

Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures

1 day 4 hours ago
Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with both familial and sporadic PD, making LRRK2 kinase inhibitors a major focus of drug development efforts. Although much progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-electron...
Marta Sanz Murillo

Exercise and gait/movement analyses in treatment and diagnosis of Parkinson's Disease

2 days 4 hours ago
Cardinal motor symptoms in Parkinson's disease (PD) include bradykinesia, rest tremor and/or rigidity. This symptomatology can additionally encompass abnormal gait, balance and postural patterns at advanced stages of the disease. Besides pharmacological and surgical therapies, physical exercise represents an important strategy for the management of these advanced impairments. Traditionally, diagnosis and classification of such abnormalities have relied on partially subjective evaluations...
Johannes Burtscher

Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease

2 days 4 hours ago
Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS...
Hyun-Sik Yang

A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains

2 days 4 hours ago
Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial...
Andras Sziraki

Dementia, osteoporosis and fragility fractures: intricate epidemiological relationships, plausible biological connections, and twisted clinical practices

3 days 4 hours ago
Dementia, osteoporosis, and fragility fractures are chronic diseases, often co-existing in older adults. These conditions pose severe morbidity, long-term disability, and mortality, with relevant socioeconomic implications. While in the research arena, the discussion remains on whether dementia is the cause or the consequence of fragility fractures, healthcare professionals need a better understanding of the interplay between such conditions from epidemiological and physiological standpoints....
C Ruggiero

Disease-specific tau filaments assemble via polymorphic intermediates

3 days 4 hours ago
Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention^(1,2). However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy to study the in vitro assembly of recombinant truncated tau (amino acid residues 297-391)...
Sofia Lövestam

Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson's disease

3 days 4 hours ago
Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson's disease (PD). Disruption of proteostasis is thought to be central to pathologic α-synuclein toxicity; however, the molecular mechanism of this deregulation is poorly understood. Complementary proteomic approaches in cellular and animal models of PD were used to identify and characterize the pathologic α-synuclein interactome. We report that the highest biological processes that...
Mohammed Repon Khan

INPP5D regulates inflammasome activation in human microglia

4 days 4 hours ago
Microglia and neuroinflammation play an important role in the development and progression of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are...
Vicky Chou

Liver X receptor alpha ensures blood-brain barrier function by suppressing SNAI2

4 days 4 hours ago
In Alzheimer's disease (AD) more than 50% of the patients are affected by capillary cerebral amyloid-angiopathy (capCAA), which is characterized by localized hypoxia, neuro-inflammation and loss of blood-brain barrier (BBB) function. Moreover, AD patients with or without capCAA display increased vessel number, indicating a reactivation of the angiogenic program. The molecular mechanism(s) responsible for BBB dysfunction and angiogenesis in capCAA is still unclear, preventing a full understanding...
D Vacondio

NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease

4 days 4 hours ago
Nicotinamide adenine dinucleotide (NAD) replenishment therapy using nicotinamide riboside (NR) shows promise for Parkinson's disease (PD) and other neurodegenerative disorders. However, the optimal dose of NR remains unknown, and doses exceeding 2000 mg daily have not been tested in humans. To evaluate the safety of high-dose NR therapy, we conducted a single-center, randomized, placebo-controlled, double-blind, phase I trial on 20 individuals with PD, randomized 1:1 on NR 1500 mg twice daily (n...
Haakon Berven

The genetic relationships between brain structure and schizophrenia

4 days 4 hours ago
Genetic risks for schizophrenia are theoretically mediated by genetic effects on brain structure but it has been unclear which genes are associated with both schizophrenia and cortical phenotypes. We accessed genome-wide association studies (GWAS) of schizophrenia (N = 69,369 cases; 236,642 controls), and of three magnetic resonance imaging (MRI) metrics (surface area, cortical thickness, neurite density index) measured at 180 cortical areas (N = 36,843, UK Biobank). Using Hi-C-coupled MAGMA, 61...
Eva-Maria Stauffer

Resting-state global brain activity affects early β-amyloid accumulation in default mode network

5 days 4 hours ago
It remains unclear why β-amyloid (Aβ) plaque, a hallmark pathology of Alzheimer's disease (AD), first accumulates cortically in the default mode network (DMN), years before AD diagnosis. Resting-state low-frequency ( < 0.1 Hz) global brain activity recently was linked to AD, presumably due to its role in glymphatic clearance. Here we show that the preferential Aβ accumulation in the DMN at the early stage of Aβ pathology was associated with the preferential reduction of global brain activity in...
Feng Han

TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease

5 days 4 hours ago
In Alzheimer's disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO ( NCT03352557 ), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab-a monoclonal antibody to N-terminal tau-in patients with early Alzheimer's disease. The primary objective was to assess the safety and tolerability of...
Melanie Shulman

TRIM22 facilitates autophagosome-lysosome fusion by mediating the association of GABARAPs and PLEKHM1

5 days 4 hours ago
Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin ligases implicated in antiviral defense systems, tumorigenesis, and protein quality control. TRIM proteins contribute to protein quality control by regulating the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and macroautophagy/autophagy. However, the detailed mechanisms through which various TRIM proteins regulate downstream events have not yet been fully elucidated. Herein, we identified a novel...
Hansol Heo

GLP-1/Sigma/RAGE Receptors: An evolving picture of Alzheimer's Disease pathology and treatment

6 days 4 hours ago
According to the facts and figures 2023 on Alzheimer's disease (AD) stated that 6.7 million Americans over the age of 65 have AD. The scenario of AD has reached up to the maximum, of 4.1 million individuals, 2/3^(rd) are female patients, and approximately 1 in 9 adults over the age of 65 have dementia with AD dementia. The fact that there are now no viable treatments for AD indicates that the underlying disease mechanisms are not fully understood. The progressive neurodegenerative illness AD is...
None Neha

Calprotectin in Parkinsonian Disease: Anticipation and Dedication

6 days 4 hours ago
Parkinson's disease (PD) is a neurodegenerative disease due to degeneration of dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc). PD is characterized by motor and non-motor symptoms. Non-motor symptoms such as constipation and dysfunction of gastrointestinal tract (GIT) motility together with medications used in the management of PD affect gut microbiota. Alterations of gut microbiota with development of gut dyspiosis can induce momentous changes in gut barrier with...
Haydar M Al-Kuraishy

ApoE Mimic Peptide COG1410 reduces Aβ deposition and improves cognitive function by inducing the transformation of A1/ A2 reactive astrocytes and increasing the BDNF concentration in brain of APP/PS1 double transgenic mice

1 week ago
The main clinical manifestation of Alzheimer's disease is progressive cognitive decline, and its pathological features are β-amyloid (Aβ) deposition, neurofibrillary tangles, synaptic dysfunction and neuron death. Neuroinflammation is an important reason for the occurrence and development of AD, which is mainly manifested by the accumulation of activated microglia and reactive astrocytes. Apolipoprotein E (ApoE) is one of the most important apolipoprotein in the brain, which is related to...
Yue Qiao
5 hours 38 minutes ago
Alzheimer and Parkinson: Latest results from PubMed
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