In Alzheimer's disease, tau is predominantly acetylated at K174, K274, K280, and K281 residues. The acetylation of K274-tau is linked with memory loss and dementia. In this study, we have examined the molecular mechanism of the toxicity of acetylated K274-tau. We incorporated an acetylation mimicking mutation at K274 (K→Q) residue of tau. The mutation (K274Q) strongly reduced the ability of tau to bind to tubulin and also to polymerize tubulin while K274R mutation did not reduce the ability of tau either to bind or polymerize tubulin. In addition, K274Q-tau displayed a higher aggregation propensity than wild-type tau as evident from thioflavin S fluorescence, tryptophan fluorescence, and electron microscopic images. Furthermore, dynamic light scattering, atomic force microscopy, and dot blot analysis using an oligomer-specific antibody suggested that K274Q mutation enhanced the oligomerization of tau. The K274Q mutation also strongly decreased the critical concentration for the liquid-liquid phase separation of tau. The oligomeric forms of K274Q-tau were found to be more toxic than wild tau to neuroblastoma cells. Using circular dichroism and fluorescence spectroscopy, we provide evidence indicating that the acetylation mimicking mutation (K274Q) induced conformational changes in tau. The results suggested that the acetylation of tau at 274 residues can increase tau aggregation and enhance the cytotoxicity of tau oligomers.

Download full-text PDF

Source
http://dx.doi.org/10.1042/BCJ20190042DOI Listing

Publication Analysis

Top Keywords

tau
14
acetylation mimicking
12
mimicking mutation
12
mutation k274q
12
tau aggregation
8
ability tau
8
tau bind
8
polymerize tubulin
8
k274q mutation
8
mutation
7

Similar Publications

Introduction: Alzheimer's disease (AD), primary age-related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all feature hyperphosphorylated tau (p-tau)-immunoreactive neurofibrillary degeneration, but differ in neuroanatomical distribution and progression of neurofibrillary degeneration and amyloid beta (Aβ) deposition.

Methods: We used Nanostring GeoMx Digital Spatial Profiling to compare the expression of 70 proteins in neurofibrillary tangle (NFT)-bearing and non-NFT-bearing neurons in hippocampal CA1, CA2, and CA4 subregions and entorhinal cortex of cases with autopsy-confirmed AD (n = 8), PART (n = 7), and CTE (n = 5).

Results: There were numerous subregion-specific differences related to Aβ processing, autophagy/proteostasis, inflammation, gliosis, oxidative stress, neuronal/synaptic integrity, and p-tau epitopes among these different disorders.

View Article and Find Full Text PDF

Tooth loss, periodontal infection and their relationship to cognitive impairment and other dementias: A review.

Neuro Endocrinol Lett

December 2024

Private Practice, Zubná Pohotovosť, s.r.o. Bratislava, Krížna 44, Slovakia.

Our review study addresses the issue of tooth loss, which is caused by loss of masticatory function and its impact on cognitive functions, dementia, and Alzheimer's disease. Numerous studies have confirmed a positive correlation between premature tooth loss, reduction in masticatory function and significant cognitive decline observed through learning disabilities, including overcoming ordinary life problems to early and advanced forms of dementia. Reduced numbers of teeth in the main food processing area, i.

View Article and Find Full Text PDF

Background: India, with the largest population and second-highest type 2 diabetes mellitus (T2DM) prevalence, presents a unique genetic landscape. This study explores the genetic profiling of T2DM, aiming to bridge gaps in existing research and provide insights for further explorations.

Methods: We conducted a systematic review and meta-analysis of literature published up to September 2024 using databases like PubMed, Web of Science, Scopus, and Google Scholar to identify SNPs associated with T2DM in case-control studies within the Indian population.

View Article and Find Full Text PDF

Background: A diagnostic criterion of Anorexia Nervosa (AN) is body image disturbance. Body exposure therapy is a widely used approach to treat this; however, it is unclear which part of body exposure therapy is relevant for regaining a realistic perspective on the own body. This study aimed to examine the role of the attentional bias (AB), which AN patients exhibit to the most disliked parts of their body.

View Article and Find Full Text PDF

Background: Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired reasoning. It is the leading cause of dementia in older adults, marked by the pathological accumulation of amyloid-beta plaques and neurofibrillary tangles. These pathological changes lead to widespread neuronal damage, significantly impacting daily functioning and quality of life.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!