Molecular brain, 2018-02, Vol.11 (1), p.7-16, Article 7
2018
Details
- Autor(en) / Beteiligte
- Titel
- 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
- Ist Teil von
- Molecular brain, 2018-02, Vol.11 (1), p.7-16, Article 7
- Ort / Verlag
- England: BioMed Central Ltd
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- Electronic Journals Library - Freely accessible e-journals
- Beschreibungen/Notizen
- 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 a therapeutic treatment that mitigates the effects of Aβ and rescue cognitive function. Here we tested the hypothesis that lentivirus-mediated expression of a human sAPPα 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 sAPPα performed significantly better than untreated littermates in all aspects of the spatial water maze task. Expression of sAPPα 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 sAPPα for 3 months from 10 months of age, or acute sAPPα treatment in hippocampal slices from 18 to 20 months old transgenic mice, completely reversed the deficits in LTP. Together these findings suggest that sAPPα has wide potential to act as either a preventative or restorative therapeutic treatment in AD by mitigating the effects of Aβ toxicity and enhancing cognitive reserve.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1756-6606eISSN: 1756-6606DOI: 10.1186/s13041-018-0348-9Titel-ID: cdi_doaj_primary_oai_doaj_org_article_829842a4c1ec4ba690c8af863cc84017
- Format
- –
- Schlagworte
- Alzheimer's disease, Amyloid, Amyloid - drug effects, Amyloid - metabolism, Amyloid beta-Peptides - metabolism, Amyloid beta-protein, Amyloid beta-Protein Precursor - administration & dosage, Amyloid beta-Protein Precursor - metabolism, Amyloid beta-Protein Precursor - pharmacology, Amyloid beta-Protein Precursor - therapeutic use, Amyloid precursor protein, Animals, Behavior, Animal, Biomarkers - metabolism, Care and treatment, Disease Models, Animal, Genetic aspects, Health aspects, Hippocampus, Hippocampus - pathology, Hippocampus - physiopathology, Humans, Lentivirus, Lentivirus - metabolism, Long-term potentiation, Long-Term Potentiation - drug effects, Male, Maze Learning - drug effects, Memory, Memory Disorders - drug therapy, Memory Disorders - pathology, Memory Disorders - physiopathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity - drug effects, Neurons - drug effects, Neurons - metabolism, Peptide Fragments - administration & dosage, Peptide Fragments - metabolism, Peptide Fragments - pharmacology, Peptide Fragments - therapeutic use, Plaque, Amyloid - pathology, Plaque, Amyloid - physiopathology, Synaptic Transmission - drug effects, Transduction, Genetic