Biology subjects

Paidi, R. K.

Publications and source records attributed to Paidi, R. K..

3 recordsLinked to original sources

bioRxiv2023

Astroglia-derived TIMP-1 alleviates cognitive deficits by restoring synaptic plasticity in Alzheimer's disease

The influence of astrocyte-secreted cytokines on neuronal health in Alzheimers disease (AD) is poorly understood, despite their increasing recognition as potential molecules for therapeutic targeting. Recently, we demonstrated that an anti-inflammatory cytokine, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is robustly secreted by astrocytes early in response to amyloid-{beta} (A{beta}) but is reduced in its prolonged presence. Here, we found strikingly diminished levels of TIMP-1 in the brain of six-month-old 5xFAD mice concomitant with high levels of A{beta}, versus wild-type mice. Intracerebroventricular injection of TIMP-1 in 5xFAD mice ameliorated their cognitive functions. TIMP-1 not only ensured neuronal viability against apoptosis and aberrant autophagy in the AD model by binding to neuronal CD63 receptors, but also conferred synapse-specific effects. Synaptosomal analysis revealed TIMP-1 elevates dendritic spine size and protein levels, likely by promoting post-synaptic long-term potentiation in hippocampus, independent of pre-synaptic activity. TIMP-1 induced brain-derived neurotrophic factor (BDNF) and BDNF-mediated post-synaptic signaling. Therefore, we identify TIMP-1 as a multifunctional cytokine with distinct protective mechanisms-of-action on neurons and propose it as a promising therapeutic candidate in AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/533245v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@187adadorg.highwire.dtl.DTLVardef@9b6ae1org.highwire.dtl.DTLVardef@185e352org.highwire.dtl.DTLVardef@10f2995_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Rheb-mTOR Activation Rescues Amyloid Beta-Induced Cognitive Impairment and Memory Function by Restoring miR-146 Activity in Glial Cells

Deposition of amyloid beta plaques in adult rat or human brain is associated with increased production of proinflammatory cytokines by associated glial cells that are responsible for degeneration of the diseased tissue. The expression of these cytokines is usually under check and is controlled at post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimers disease patients brain suggests ineffective target cytokine mRNA suppression by existing microRNPs in diseased brain. Exploring the mechanism of amyloid beta induced cytokine expression, we have identified how the inactivation of the repressive miR-146 microRNPs causes increased production of cytokines in amyloid beta exposed glial cells. In exploration of the cause of miRNP inactivation, we have noted amyloid beta oligomer induced sequestration of mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling and retarded Ago2-cytokine mRNA interaction in rat astrocyte cells. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 microRNPs in amyloid beta exposed glial cells to rescue the disease phenotype in the in vivo rat model of Alzheimers disease.

neuroscience↗

bioRxiv2020

Fruit bromelain derived peptides destabilize growth of amyloidal fibrils

{beta}-Amyloid deposition as fibrillar plaques in brain is the primary cause of Alzheimers disease. We report potency of cysteine protease fruit bromelain from pineapple in destabilising A{beta} fibrils. Bromelain peptide pool (Mw<500 Da) obtained mimicking human alimentary tract digestion inhibited fibrillation from monomeric and oligomeric states of A and irreversibly dissociated preformed fibrils into small oligomers of varied sizes. Time kinetics was followed by Thioflavin-T assay and microscopic imaging. Synthetic bromelain peptides corresponding to A{beta} sticky region found using ClustalW analysis revealed specificity of peptides in destabilisation of amyloidal structures. Spectra of different molecular states of A{beta} obtained from application of 8-anilino-1-naphthalenesulfonic acid, circular dichroism and Fourier-Transformed Infrared spectroscopy collectively indicated interaction dependent structural change. Probable mechanism for fibril dissociation was thus predicted. Peptides relieved A{beta} cytotoxicity on pheochromcytoma cells and dissociated plaques in AD-type rats prepared by bilateral intracerebroventricular administration of A{beta} in rat brain cortex. Pineapple being a phytoceutical, its efficiency to disaggregate amyloid bodies warrant further investigation. GRAPHICAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biochemistry↗