sAPPα Over-Expression as a Preventative Measure Against Alzheimer’s Disease in a Mouse Model

Abstract

Alzheimer’s disease (AD) is neurodegenerative disease that mainly occurs in the aging population. It manifests itself as dementia, which is a term that describes a range of behavioural changes such as memory loss, cognitive impairments and personality disturbances. AD pathology is characterized by the accumulation of insoluble amyloid β-peptide (Aβ) when amyloid precursor protein (APP) cleavage is shifted away from the non-amyloidogenic pathway towards the amyloidogenic pathway. This not only causes an increase in Aβ production, but also decreases the production of another protein, soluble amyloid precursor protein alpha (sAPPα), which is derived from the non-amyloidogenic pathway. sAPPα has been reported to have neuroprotective, neurotrophic, and neurogenic properties, and it has been suggested that this reduction in sAPPα contributes to the pathogenesis of AD. Hence increasing sAPPα in the AD brain may have therapeutic potential. However, previous methods attempting to increase sAPPα levels are either short-lived (injections) or impractical to implement (genetic manipulations). The principal aim of this thesis was to use a lentiviral vector with a synapsin promoter containing sAPPα to induce sAPPα over-expression in neurons in a mouse model of AD (APP/PS1). Mice were given bilateral intrahippocampal injections at 4 months of age, before the manifestation of AD-like symptoms and pathology. At 12 months of age, after the reported time of symptom onset, animals underwent a battery of behavioural tests, and were subsequently euthanised for electrophysiology and post-mortem analyses. Transgenic APP/PS1 mice overexpressing sAPPα performed significantly better than untreated littermates in all aspects of the water maze task. sAPPα treatment also resulted in partial treatment effects of paired-pulse inhibition and long-term potentiation. However, post-mortem analyses did not show that pathology was altered by sAPPα treatment. The findings of the current study suggest that lentiviral mediated sAPPα overexpression applied at a young age was long-lasting and sufficient to protect against some of the cognitive and synaptic deficits of AD. Therefore, sAPPα may have therapeutic potential in protecting against AD even before the disease pathology manifestation.