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Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease driven in large part by accumulated deposits in the brain of the amyloid precursor protein (APP) cleavage product amyloid-? peptide (A?). However, AD is also characterised by reductions in secreted amyloid precursor protein-alpha (sAPP?), an alternative cleavage product of APP. In contrast to the neurotoxicity of accumulated ??, sAPP? has many neuroprotective and neurotrophic properties. Increasing sAPP? levels has the potential to serve as a therapeutic treatment that mitigates the effects of A? and rescue cognitive function. Here we tested the hypothesis that lentivirus-mediated expression of a human sAPP? construct in a mouse model of AD (APPswe/PS1dE9), begun before the onset of plaque pathology, could prevent later behavioural and electrophysiological deficits. Male mice were given bilateral intra-hippocampal injections at 4 months of age and tested 8-10 months later. Transgenic mice expressing sAPP? performed significantly better than untreated littermates in all aspects of the spatial water maze task. Expression of sAPP? also resulted in partial rescue of long-term potentiation (LTP), tested in vitro. These improvements occurred in the absence of changes in amyloid pathology. Supporting these findings on LTP, lentiviral-mediated expression of sAPP? for 3 months from 10 months of age, or acute sAPP? treatment in hippocampal slices from 18 to 20 months old transgenic mice, completely reversed the deficits in LTP. Together these findings suggest that sAPP? has wide potential to act as either a preventative or restorative therapeutic treatment in AD by mitigating the effects of A? toxicity and enhancing cognitive reserve.

SUBMITTER: Tan VTY

PROVIDER: S-EPMC5806250 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease.

Tan Valerie T Y VTY Mockett Bruce G BG Ohline Shane M SM Parfitt Karen D KD Wicky Hollie E HE Peppercorn Katie K Schoderboeck Lucia L Yahaya Mohamad Fairuz Bin MFB Tate Warren P WP Hughes Stephanie M SM Abraham Wickliffe C WC

Molecular brain 20180209 1

Alzheimer's disease (AD) is a neurodegenerative disease driven in large part by accumulated deposits in the brain of the amyloid precursor protein (APP) cleavage product amyloid-β peptide (Aβ). However, AD is also characterised by reductions in secreted amyloid precursor protein-alpha (sAPPα), an alternative cleavage product of APP. In contrast to the neurotoxicity of accumulated Αβ, sAPPα has many neuroprotective and neurotrophic properties. Increasing sAPPα levels has the potential to serve as ...[more]

PMID: 29426354

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Project description:Although lots of new drugs are developed to treat Alzheimer's disease (AD), many clinical trials of monotherapy have failed to affect disease progression or symptoms compared with placebo. Recently, scientists believe that combination treatment is more promising than monotherapy. Previous studies found that microRNA-195 (miR-195) was down-regulated in the hippocampi and cortices of chronic brain hypoperfusion (CBH) rats and ApoE4(+/+) mice, and up-regulation of miR-195 can improve the declined cognitive function of ApoE4(+/+) mice and CBH rats by targeting multi-genes that are related to AD pathology, including amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) genes. However, whether the gain-of-function of miR-195 could improve the impaired learning and memory ability of APP/PS1 transgenic mouse has not been reported. In this study, we stereotaxically injected lentiviral-carried miR-195 into the bilateral hippocampus of 4-month-old (4M) APP/PS1 mice. Morris water maze (MWM) was performed to detect the effect of miR-195 on the cognitive function of APP/PS1 mice after 1M, 2M, and 3M treatment. Western blot was used to detect the expression of APP, BACE1, and AT8. Aβ plagues were quantitatively assessed by immunofluorescence technique. We found that the declined cognitive phenotype of APP/PS1 mice occurred at the age of 6M, not at the age of 5M. And treatment of Lv-pre-miR-195 to APP/PS1 mice for 1M did not achieve any changes. Although Lv-pre-miR-195 treatment for 2M improved the declined learning ability of APP/PS1 mice, it did not affect the memory functions. However, Lv-pre-miR-195 treatment in APP/PS1 mice for 3M can effectively improve both the learning and memory ability of APP/PS1 mice at the age of 7M. Further studies demonstrated that gain-of-function of miR-195 by Lv-pre-miR-195 injection could inhibit the increased APP and AT8 expression of APP/PS1 mice but did not affect BACE1 level that was not changed in both hippocampus and cortex. By counting the number of Aβ plaques of different sizes, we found that Lv-pre-miR-195 treatment mainly reduced the number of Aβ plaques of less than 20 μm, but did not affect the number of Aβ plaques of greater than 50 μm. Taken together, the gain-of -function of miR-195 in the hippocampus can improve the cognition of APP/PS1 mice, probably by blocking the formation of Aβ plagues rather than clearing those that have already formed Aβ plagues.

Dataset Information

Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease.

Publications

Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease.

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