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Hippocampal expression of murine TNF? results in attenuation of amyloid deposition in vivo.

ABSTRACT: Fibrillar amyloid ? (fA?) peptide is the major component of A? plaques in the brains of Alzheimer's disease (AD) patients. Inflammatory mediators have previously been proposed to be drivers of A? pathology in AD patients by increasing amyloidogenic processing of APP and promoting A? accumulation, but recent data have shown that expression of various inflammatory cytokines attenuates A? pathology in mouse models. In an effort to further study the role of different inflammatory cytokines on A? pathology in vivo, we explored the effect of murine Tumor Necrosis Factor ? (mTNF?) in regulating A? accumulation. Recombinant adeno-associated virus serotype 1 (AAV2/1) mediated expression of mTNF? in the hippocampus of 4 month old APP transgenic TgCRND8 mice resulted in significant reduction in hippocampal A? burden. No changes in APP levels or APP processing were observed in either mTNF? expressing APP transgenic mice or in non-transgenic littermates. Analysis of A? plaque burden in mTNF? expressing mice showed that even after substantial reduction compared to EGFP expressing age-matched controls, the A? plaque burden levels of the former do not decrease to the levels of 4 month old unmanipulated mice. Taken together, our data suggests that proinflammatory cytokine expression induced robust glial activation can attenuate plaque deposition. Whether such an enhanced microglial response actually clears preexisting deposits without causing bystander neurotoxicity remains an open question.

SUBMITTER: Chakrabarty P

PROVIDER: S-EPMC3050766 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo.

Chakrabarty Paramita P Herring Amanda A Ceballos-Diaz Carolina C Das Pritam P Golde Todd E TE

Molecular neurodegeneration 20110216

Fibrillar amyloid β (fAβ) peptide is the major component of Aβ plaques in the brains of Alzheimer's disease (AD) patients. Inflammatory mediators have previously been proposed to be drivers of Aβ pathology in AD patients by increasing amyloidogenic processing of APP and promoting Aβ accumulation, but recent data have shown that expression of various inflammatory cytokines attenuates Aβ pathology in mouse models. In an effort to further study the role of different inflammatory cytokines on Aβ pat ...[more]

PMID: 21324189

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Project description:BackgroundAlzheimer's disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice.MethodsAPP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior.ResultsIn APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed.ConclusionsApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

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Hippocampal expression of murine TNF? results in attenuation of amyloid deposition in vivo.

Publications

Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo.

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