Protein phosphatase-2A (PP2A) deficiency is a cause of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. We previously reported that both mRNA and protein expression of inhibitor I of PP2A (I(1)(PP2A)) are elevated in AD brain and that this inhibitor induces a dose-dependent inhibition of PP2A activity and tau hyperphosphorylation in NIH3T3 cells. However, whether I(1)(PP2A) can induce AD neurofibrillary degeneration and cognitive impairment was not known. In the present study, we infected the brains of rat pups within 24 hours of birth with adeno-associated virus serotype 1 (AAV1) carrying I(1)(PP2A). In the adult AAV1-I(1)(PP2A) rats, we found a decrease in PP2A activity and abnormal hyperphosphorylation of tau in the brain. Immunohistochemistry showed a significant reduction of MAP2 and synapsin 1 in AAV1- I(1)(PP2A) animals, suggesting that I(1)(PP2A) can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I(1)(PP2A) induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I(1)(PP2A) can inhibit PP2A activity, and in turn induce AD neurofibrillary degeneration and cognitive deficits in rats.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.3233/JAD-142403 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Evaluating the Efficacy of Levetiracetam on Non-Cognitive Symptoms and Pathology in a Tau Mouse Model.
Biomedicines
December 2024
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA.
Alzheimer's disease (AD) is marked by amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs), leading to cognitive decline and debilitating non-cognitive symptoms. This study aimed to evaluate compounds from four different classes in a short-term (7-day) study using transgenic tau mice to assess their ability to reduce non-cognitive symptoms. The best candidate was then evaluated for longer exposure to assess non-cognitive symptoms, cognition, and pathology.
View Article and Find Full Text PDFExploring the Complex Relationship Between Antidepressants, Depression and Neurocognitive Disorders.
Biomedicines
November 2024
Department of Clinical Neurosciences, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania.
The coexistence of dementia and depression in older populations presents a complex clinical challenge, with each condition often exacerbating the other. Cognitive decline can intensify mood disturbances, and untreated or recurring depression accelerates neurodegenerative processes. As depression is a recognized risk factor for dementia, it is crucial to address both conditions concurrently to prevent further deterioration.
View Article and Find Full Text PDFRole of Microbiota-Derived Hydrogen Sulfide (HS) in Modulating the Gut-Brain Axis: Implications for Alzheimer's and Parkinson's Disease Pathogenesis.
Biomedicines
November 2024
Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy "Grigore T. Popa", 700454 Iasi, Romania.
Microbiota-derived hydrogen sulfide (HS) plays a crucial role in modulating the gut-brain axis, with significant implications for neurodegenerative diseases such as Alzheimer's and Parkinson's. HS is produced by sulfate-reducing bacteria in the gut and acts as a critical signaling molecule influencing brain health via various pathways, including regulating inflammation, oxidative stress, and immune responses. HS maintains gut barrier integrity at physiological levels and prevents systemic inflammation, which could impact neuroinflammation.
View Article and Find Full Text PDFRosemarinic Acid-Induced Destabilization of Aβ Peptides: Insights from Molecular Dynamics Simulations.
Foods
December 2024
Key Laboratory of Geriatric Nutrition and Health, Beijing Technology and Business University, Ministry of Education, Beijing 100048, China.
Alzheimer's disease (AD) is a neurodegenerative disorder marked by the progressive accumulation of amyloid-β (Aβ) plaques and tau protein tangles in the brain. These pathological aggregates interfere with neuronal function, leading to the disruption of cognitive processes, particularly memory. The deposition of Aβ forms senile plaques, while tau protein, in its hyperphosphorylated state, forms neurofibrillary tangles, both of which contribute to the underlying neurodegeneration observed in AD.
View Article and Find Full Text PDFBMAL1 ameliorates type 2 diabetes-induced cognitive impairment via AREG upregulation and PI3K/Akt/GSK-3β pathway activation.
Cell Commun Signal
January 2025
Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Cognitive impairment is a significant complication of type 2 diabetes mellitus (T2DM). However, the mechanisms underlying the development of cognitive dysfunction in individuals with T2DM remain elusive. Herein, we discussed the role of Bmal1, a core circadian rhythm-regulating gene, in the process of T2DM-associated cognitive dysfunction.
View Article and Find Full Text PDFWant 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!