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

Emergence of synaptic and cognitive dysfunction in an inducible mouse model of Alzheimer's disease
Emergence of synaptic and cognitive dysfunction in an inducible mouse model of Alzheimer's disease
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 APPSwe/Ind expression in adult mice at six weeks of age. We show that three-weeks of APPSwe/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 APPSwe/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 APPSwe/Ind expression. We also found that by suppressing further expression of the APPSwe/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 APPSwe/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 APPSwe/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.
University of Southampton
Sri, Sarmi
ed51da26-76c4-45ff-95ab-5aa3bc7d7583
Sri, Sarmi
ed51da26-76c4-45ff-95ab-5aa3bc7d7583
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1

Sri, Sarmi (2018) Emergence of synaptic and cognitive dysfunction in an inducible mouse model of Alzheimer's disease. University of Southampton, Doctoral Thesis, 258pp.

Record type: Thesis (Doctoral)

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 APPSwe/Ind expression in adult mice at six weeks of age. We show that three-weeks of APPSwe/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 APPSwe/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 APPSwe/Ind expression. We also found that by suppressing further expression of the APPSwe/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 APPSwe/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 APPSwe/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.

Text
Sarmi Sri FINAL_Thesis - Version of Record
Restricted to Repository staff only until 31 March 2021.
Available under License University of Southampton Thesis Licence.

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Published date: January 2018

Identifiers

Local EPrints ID: 419012
URI: http://eprints.soton.ac.uk/id/eprint/419012
PURE UUID: 3f1448ad-b13a-461a-a288-b022ef237b2b
ORCID for Mariana Vargas-Caballero: ORCID iD orcid.org/0000-0003-2326-4001

Catalogue record

Date deposited: 28 Mar 2018 16:30
Last modified: 14 Mar 2019 01:35

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