Project description:Amyloid plaques and neurofibrillary tangles are present in the brains of individuals with intact memory function. The study of these brains can open new avenues to identify new therapeutic targets. This experriment aimed to identified genes contributing to maintain an intact memory in the presence of AD pathology.
Project description:The mechanisms underlying age-associated memory impairment are not well understood. We have shown that the onset of memory disturbances in the aging brain is associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation. To analyze if deregulated H4K12 acetylation impacts on learning-induced gene-expression required for memory consolidation we performed a high-density oligonucleotide microarray to compare the entire hippocampal gene-expression profile of 3 and 16-month-old mice during memory consolidation. In order to identify genes differentially regulated between 3- and 16-month old mice upon fear conditioning we subjected 3- and 16-month old mice to fear conditioning (4 mice each group, total 8 mice) . Mice of the same age that were handled but not subjected to any of the employed behavior paradigms served as control (4 mice 3-month old and 4 mice 16-month old, total 8 mice). During fear conditioning mice are subjected to a novel context followed by a mild electric foot-shock (context-shock exposure). In order to identify genes that are differentially regulated upon fear conditioning and are specific to associative learning we also tested the hippocampal gene-expression profile of 3-month old mice subjected to the same context-exposure that is not followed by a foot-shock (Context-exposure) (4 mice) or receive an immediate foot shock once they are placed in the context and only afterwards are allowed to explore the context (shock-context exposure) (4 mice). In order to identify genes that are regulated upon fear conditioning and are specific to associative learning we compared the hippocampal gene-expression profile of mice subjected to fear conditioning (context-shock), context or shock-context exposure regarding to their age-matched control mice (3 month old) mentioned above (control). Hippocampi from each mice were tested resulting to 24 samples which were separately hybridized (OneColor Array Design).
Project description:Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. In AD, neurodegeneration spreads throughout the brain cortex in a gradual and predictable pattern, causing progressive memory decline and cognitive impairment. Here, we conducted proteomic, acetylomic and phosphoproteomic analyses of human postmortem tissue samples from AD (Braak stage III-IV) and control brains, covering all anatomical areas affected during the limbic stage of the disease (total hippocampus, CA1, entorhinal and perirhinal cortices). A total of 58 tissues were analyzed by nanoLC-MS/MS.
Project description:The dynamic function of synapses is critical for encoding memories in the brain. Pathogenic tau obstructs glutamatergic synapse function by blocking long-term potentiation (LTP), representing a key mechanism underlying memory impairment in Alzheimer s disease (AD). Here we developed a strategy for KIdney/BRAin (KIBRA)-mediated LTP repair in neurons with pathogenic tau using the C-terminus of KIBRA (CT-KIBRA). We show that CT-KIBRA restores LTP and memory in transgenic mice expressing human tau that mimics pathogenic hyperacetylated tau found in AD and other tauopathies. CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss in the transgenic mouse brain, instead, we show that CT-KIBRA binds to and stabilizes protein kinase M zeta (PKM zeta) to maintain plasticity and memory despite tau pathogenesis. Further, in humans we established that KIBRA levels in brain and cerebrospinal fluid correlate with tau and cognitive impairment in tauopathies. Our study provides evidence to support KIBRA as a tauopathy-related synaptic biomarker and a synapse repair therapeutic to ameliorate cognitive impairment.
Project description:Growing evidence implicates transposable elements (TEs) in aging and Alzheimer’s disease (AD). To evaluate potential transcriptional and epigenetic differences related to TE expression in this context, we generated whole blood total RNA-seq, and peripheral blood cell whole-genome bisulfite sequencing (WGBS), and transposase-accessible chromatin sequencing (ATAC-seq) on samples from healthy middle-aged/older adults, mild cognitive impairment (MCI), and AD patients.
Project description:The mechanisms underlying age-associated memory impairment are not well understood. We have shown that the onset of memory disturbances in the aging brain is associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation. To analyze if deregulated H4K12 acetylation impacts on learning-induced gene-expression required for memory consolidation we performed a high-density oligonucleotide microarray to compare the entire hippocampal gene-expression profile of 3 and 16-month-old mice during memory consolidation.
Project description:Based on behavioral paradigms, olfactory memory impaiment was considered as the first congnitive decline symptom in 5xFAD mice at 4-month-old. Proteomes in olfactory memory associated brain region, piriform cortex, at different stages were analyzed. The results indiciated that proteins alterations at different stages are diverse, but the core regulatory network involved in AD pathogenesis is conservd. Microglia and astrocyte specific proteins are enriched in the networks and associated with glial cell activation in the initial cognitive impairment stage. It implied the mutual effect of the two glial cells plays an essential role in Aβ induced initial AD pathogenesis.
Project description:Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRNAs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of amnestic mild cognitive impairment (aMCI) and AD patients. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it didn't affect the Aβ levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.