Dataset Information

PGC-1? or FNDC5 Is Involved in Modulating the Effects of A?1-42 Oligomers on Suppressing the Expression of BDNF, a Beneficial Factor for Inhibiting Neuronal Apoptosis, A? Deposition and Cognitive Decline of APP/PS1 Tg Mice.

ABSTRACT: Alzheimer's disease (AD) is generally defined as the aberrant production of ?-amyloid protein (A?) and hyperphosphorylated tau protein, which are deposited in ?-amyloid plaques (APs) and neurofibrillary tangles (NFTs), respectively. Decreased levels of brain-derived neurotrophic factor (BDNF) have been detected in patients with AD compared to control subjects. However, the underlying molecular mechanisms driving the downregulation of the BDNF remain unknown. Therefore, we explored the mechanisms underlying the regulation of BDNF in the neurons of APP/PS1 transgenic (Tg) mice, an AD experimental model. Using the APP/PS1 Tg mice, we found that BDNF expression was markedly downregualted at the age of 3- and 9-month-old. After cerebroventricular injection (i.c.v) of A?1-42 oligomers into the mice, BDNF was also found to be decreased, which demonstrated the critical roles of the A?1-42 oligomers in regulating the expression of BDNF. In neuronal culture, peroxisome proliferators-activated receptor ? coactivator 1? (PGC-1?) and fibronectin type III domain-containing 5 (FNDC5) were found to be downregulated by treatment with the A?1-42 oligomers. In addition, overexpression of either PGC-1? or FNDC5 reversed the suppressive effects of the A?1-42 oligomers on the expression of BDNF in neuroblastoma 2a (n2a) cells. More importantly, elevating the levels of PGC-1?, FNDC5 or BDNF in the n2a cells counteracted the effects of the A?1-42 oligomers on neuronal apoptosis. Additionally, intranasal administration BDNF in the APP/PS1 Tg mice decreased the A? deposition and reduced the cognitive decline of the mice.

SUBMITTER: Xia DY

PROVIDER: S-EPMC5359257 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PGC-1α or FNDC5 Is Involved in Modulating the Effects of Aβ<sub>1-42</sub> Oligomers on Suppressing the Expression of BDNF, a Beneficial Factor for Inhibiting Neuronal Apoptosis, Aβ Deposition and Cognitive Decline of APP/PS1 Tg Mice.

Xia De-Yu DY Huang Xin X Bi Chong-Feng CF Mao Lin-Ling LL Peng Li-Jun LJ Qian Hai-Rong HR

Frontiers in aging neuroscience 20170321

Alzheimer's disease (AD) is generally defined as the aberrant production of β-amyloid protein (Aβ) and hyperphosphorylated tau protein, which are deposited in β-amyloid plaques (APs) and neurofibrillary tangles (NFTs), respectively. Decreased levels of brain-derived neurotrophic factor (BDNF) have been detected in patients with AD compared to control subjects. However, the underlying molecular mechanisms driving the downregulation of the BDNF remain unknown. Therefore, we explored the mechanisms ...[more]

PMID: 28377712

Similar Datasets

Project description:BackgroundAlzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD.MethodsHippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aβ-treated HEBSCs.ResultsNeurotoxicity induced by soluble Aβ1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention.ConclusionMicroglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity.

Dataset Information

PGC-1? or FNDC5 Is Involved in Modulating the Effects of A?1-42 Oligomers on Suppressing the Expression of BDNF, a Beneficial Factor for Inhibiting Neuronal Apoptosis, A? Deposition and Cognitive Decline of APP/PS1 Tg Mice.

Publications

PGC-1α or FNDC5 Is Involved in Modulating the Effects of Aβ<sub>1-42</sub> Oligomers on Suppressing the Expression of BDNF, a Beneficial Factor for Inhibiting Neuronal Apoptosis, Aβ Deposition and Cognitive Decline of APP/PS1 Tg Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets