Dataset Information

Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1.

ABSTRACT: Alzheimer's disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of ?-amyloid (A?) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of A? peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of A? peptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression. This review will focus on the antioxidant and anti-inflammatory neuroprotective effects of resveratrol, specifically on its role in SIRT1 and the association with AD pathophysiology.

SUBMITTER: Gomes BAQ

PROVIDER: S-EPMC6232815 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1.

Gomes Bruno Alexandre Quadros BAQ Silva João Paulo Bastos JPB Romeiro Camila Fernanda Rodrigues CFR Dos Santos Sávio Monteiro SM Rodrigues Caroline Azulay CA Gonçalves Pricila Rodrigues PR Sakai Joni Tetsuo JT Mendes Paulo Fernando Santos PFS Varela Everton Luiz Pompeu ELP Monteiro Marta Chagas MC Monteiro Marta Chagas MC

Oxidative medicine and cellular longevity 20181030

Alzheimer's disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of β-amyloid (Aβ) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aβ peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, ant ...[more]

PMID: 30510627

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Project description:Recent evidences suggest that cerebellar degeneration may be associated with the development of Alzheimer's disease (AD). However, previous reports were mainly observational, lacking substantial characterization of cellular and molecular cerebellar features during AD progression.This study is aimed at characterizing the cerebellum in rat models of AD and assessing the corresponding neuroprotective mechanisms of Garcinia biflavonoid complex (GBc).Male Wistar rats were grouped and treated alone or in combination with PBS (ad libitum)/day, corn oil (CO; 2 mL/kgBw/day), GBc (200 mg/kgBw/day), sodium azide (NaN3) (15 mg/kgBw/day) and aluminium chloride (AlCl3) (100 mg/kgBw/day). Groups A and B received PBS and CO, respectively; C received GBc; D received NaN3; E received AlCl3; F received NaN3 then GBc subsequently; G received AlCl3 then GBc subsequently; H received NaN3 and GBc simultaneously while I received AlCl3 and GBc simultaneously. Following treatments, cerebellar cortices were processed for histology, immunohistochemistry and colorimetric assays.Our data revealed that cryptic granule neurons and pyknotic Purkinje cell bodies (characterized by short dendritic/axonal processes) correspond to indistinctly demarcated cerebellar layers in rats treated with AlCl3 and NaN3. These correlates, with observed hypertrophic astrogliosis, increased the neurofilament deposition, depleted the antioxidant system-shown by expressed superoxide dismutase and glutathione peroxidase, and cerebellar glucose bioenergetics dysfunction-exhibited in assayed lactate dehydrogenase and glucose-6-phosphate dehydrogenase. We further showed that GBc reverses cerebellar degeneration through modulation of neurochemical signaling pathways and stressor molecules that underlie AD pathogenesis.Cellular, molecular and metabolic neurodegeneration within the cerebellum is associated with AlCl3 and NaN3-induced AD while GBc significantly inhibits corresponding neurotoxicity and is more efficacious when pre-administered.

Project description:The progressive neurodegenerative disorder Alzheimer's disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (A?42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The A?42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for A?42 mediated neurodegeneration is yet to be fully understood.We have utilized Gal4/UAS system to develop a transgenic fruit fly model for A?42 mediated neurodegeneration. Targeted misexpression of human A?42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer's like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of A?42 mediated neurodegeneration. Targeted misexpression of CBP along with A?42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues A?42 mediated neurodegeneration by blocking cell death. Misexpression of A?42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with A?42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.We have identified CBP as a genetic modifier of A?42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.

Dataset Information

Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1.

Publications

Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1.

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