In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117511 | PLOS |
Alzheimers Dement
December 2024
Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Introduction: Aggregation of hyperphosphorylated tau (tauopathy) is associated with cognitive impairment in patients with Alzheimer's disease (AD). In AD, a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification (PTM) on proteins that conjugates lactyl groups to lysine (K) residues, which is known as lactylation.
View Article and Find Full Text PDFMol Neurodegener
December 2024
German Center for Neurodegenerative Diseases (LMU), Klinikum, Germany.
Background: The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research indicates that human neurons internalize both the physiological extracellular Tau (eTau) monomers and the pathological eTau aggregates.
View Article and Find Full Text PDFJ Integr Neurosci
December 2024
Department of Human Anatomy, School of Basic Medical Sciences, Wannan Medical College, 241002 Wuhu, Anhui, China.
Background: K48-linked ubiquitin chain (Ub-K48) is a crucial ubiquitin chain implicated in protein degradation within the ubiquitin-proteasome system. However, the precise function and molecular mechanism underlying the role of Ub-K48 in the pathogenesis of Alzheimer's disease (AD) and neuronal cell abnormalities remain unclear. The objective of this study was to examine the function of K48 ubiquitination in the etiology of AD, and its associated mechanism of neuronal apoptosis.
View Article and Find Full Text PDFPharmacol Res
December 2024
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, Italy. Electronic address:
Alzheimer's disease, the leading cause of dementia globally, represents an unresolved clinical challenge due to its complex pathogenesis and the absence of effective treatments. Considering the multifactorial etiology of the disease, mainly characterized by the accumulation of amyloid β plaques and neurofibrillary tangles of tau protein, we discuss the A673V mutation in the gene coding for the amyloid precursor protein, which is associated with the familial form of Alzheimer's disease in a homozygous state. The mutation offers new insights into the molecular mechanisms of the disease, particularly regarding the contrasting roles of the A2V and A2T mutations in amyloid β peptide aggregation and toxicity.
View Article and Find Full Text PDFEur J Med Chem
December 2024
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sinai University, Kantara Branch, Ismailia, 41636, Egypt.
Alzheimer's disease (AD) is primarily caused by oxidative stress, hyperphosphorylated τ-protein aggregation, and amyloid-β deposition. Changes in dopaminergic and serotoninergic neurotransmitter pathways are linked to certain symptoms of AD. Derivatives of bicyclic and tricyclic cyclohepta[b]thiophene were developed to identify new potential candidates as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors for the treatment of AD.
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