Emergence of synaptic and cognitive dysfunction in an inducible mouse model of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is the world’s leading cause of dementia. Proposed therapies for AD have so far proven to be unsuccessful during clinical trials testing. This is postulated to be because these therapies focus on patients at the mid- to late-stages of pathology, following extensive and most likely irreversible damage to the brain. It is now clear that a number of key pathological events, such as synapse loss, occur prior to the emergence of any conspicuous symptoms. These early stages of AD, termed pre-clinical AD and mild cognitive impairment (MCI), are becoming increasingly attractive from a therapeutic point of view, as they allow more scope for successfully halting AD progression and potentially reversing early pathology.

In this thesis, we characterise the emergence of cognitive and synaptic dysfunction within an adult-onset model of AD. We utilise the inducible tet-off system present within the line102 model to initiate APP_Swe/Ind expression in adult mice at six weeks of age. We show that three-weeks of APP_Swe/Ind expression is sufficient to drive a deficit in short-term memory, when assessed using spontaneous alternation on the T-maze. Due to a high level of thigmotaxic behaviour observed on the Morris watermaze, spatial reference memory was assessed using the aversive swim Y-maze, a task which is not confounded by thigmotaxis. We show that 12 weeks of APP_Swe/Ind expression is sufficient to drive a deficit in long-term memory.

We performed electrophysiological field recordings to assess synaptic function within the CA3-CA1 pathway. We show that long-term potentiation is significantly impaired following three weeks of APPSwe/Ind expression, and although there was a trend in reduced input-output response at this time point, a significant difference in basal synaptic transmission was not evident till 12 weeks of APP_Swe/Ind expression. We also found that by suppressing further expression of the APP_Swe/Ind transgene, we not only reduced Aβ to non-transgenic levels but also reversed the early deficit in synaptic plasticity observed following 3 weeks of APP_Swe/Ind expression.

Thus, in this thesis, we have successfully identified a time frame during which we observe the emergence of both cognitive and synaptic dysfunction within an adult-onset model of AD. We show that 3 weeks, but not 2 weeks, of APP_Swe/Ind expression is sufficient to drive a deficit in short-term memory and synaptic plasticity. The work we present here paves the way for future work to dissect molecular changes that underlie early AD pathology, possibly even modelling what may be transpiring in individuals with MCI and/or early AD.

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Identifiers

ORCID for Mariana Vargas-Caballero: orcid.org/0000-0003-2326-4001

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