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Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer’s disease

Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer’s disease
Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer’s disease
The synaptic changes underlying the onset of cognitive impairment in Alzheimer’s disease (AD) are poorly understood. In contrast to the well documented inhibition of long-term potentiation (LTP) in CA3-CA1 synapses by acute Aβ application in adult neurons from rodents, young amyloid precursor protein (APP) transgenic mouse models often, surprisingly, show normal LTP. This suggests that there may be important differences between mature-onset and developmental-onset APP expression/ A accumulation and the ensuing synaptic and behavioural phenotype. Here, in agreement with previous studies, we observed that developmental expression of APPSw,Ind (3-4 month old mice from line 102, Jankowsky et al 2005), resulted in reduced basal synaptic transmission in CA3-CA1 synapses, normal LTP, impaired spatial working memory, but normal spatial reference memory. To analyse early A-mediated synaptic dysfunction and cognitive impairment in a more mature brain, we used controllable mature-onset APPSw,Ind expression in line 102 mice. Within 3 weeks of mature-onset APPSw,Ind expression and A accumulation, we detected the first synaptic dysfunction: an impairment of LTP in hippocampal CA3-CA1 synapses. Cognitively, at this time point, we observed a deficit in short-term memory. A reduction in basal synaptic strength and deficit in long-term associative spatial memory were only evident following 12 weeks of APPSw,Ind expression. Importantly, the plasticity impairment observed after 3 weeks of mature-onset APP expression is reversible. Together, these findings demonstrate important differences between developmental and mature-onset APP expression. Further research targeted at this early stage of synaptic dysfunction could help identify mechanisms to treat cognitive impairment in mild cognitive impairment (MCI) and early AD.
2051-5960
Sri, Sarmi
ed51da26-76c4-45ff-95ab-5aa3bc7d7583
Pegasiou, Chrysia-Maria
70534d16-7533-40c3-b017-2840366f6618
Cave, Chantal-Abbigail
e0012884-5c78-43c6-b710-8f230ab98e79
Hough, Katie
347fcb00-8b5c-40b3-8349-f87104f1d150
Wood, Natalie
4edcfcf0-0c26-47cf-811b-8a80c4449acb
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Bannerman, David
6862d768-24c0-4735-a13a-2236c4a12a01
Perry, Victor
8f29d36a-8e1f-4082-8700-09483bbaeae4
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Sri, Sarmi
ed51da26-76c4-45ff-95ab-5aa3bc7d7583
Pegasiou, Chrysia-Maria
70534d16-7533-40c3-b017-2840366f6618
Cave, Chantal-Abbigail
e0012884-5c78-43c6-b710-8f230ab98e79
Hough, Katie
347fcb00-8b5c-40b3-8349-f87104f1d150
Wood, Natalie
4edcfcf0-0c26-47cf-811b-8a80c4449acb
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Deinhardt, Katrin
5f4fe23b-2317-499f-ba6d-e639a4885dc1
Bannerman, David
6862d768-24c0-4735-a13a-2236c4a12a01
Perry, Victor
8f29d36a-8e1f-4082-8700-09483bbaeae4
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1

Sri, Sarmi, Pegasiou, Chrysia-Maria, Cave, Chantal-Abbigail, Hough, Katie, Wood, Natalie, Gomez-Nicola, Diego, Deinhardt, Katrin, Bannerman, David, Perry, Victor and Vargas-Caballero, Mariana (2019) Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer’s disease. Acta Neuropathologica Communications, 7 (25). (doi:10.1186/s40478-019-0670-1).

Record type: Article

Abstract

The synaptic changes underlying the onset of cognitive impairment in Alzheimer’s disease (AD) are poorly understood. In contrast to the well documented inhibition of long-term potentiation (LTP) in CA3-CA1 synapses by acute Aβ application in adult neurons from rodents, young amyloid precursor protein (APP) transgenic mouse models often, surprisingly, show normal LTP. This suggests that there may be important differences between mature-onset and developmental-onset APP expression/ A accumulation and the ensuing synaptic and behavioural phenotype. Here, in agreement with previous studies, we observed that developmental expression of APPSw,Ind (3-4 month old mice from line 102, Jankowsky et al 2005), resulted in reduced basal synaptic transmission in CA3-CA1 synapses, normal LTP, impaired spatial working memory, but normal spatial reference memory. To analyse early A-mediated synaptic dysfunction and cognitive impairment in a more mature brain, we used controllable mature-onset APPSw,Ind expression in line 102 mice. Within 3 weeks of mature-onset APPSw,Ind expression and A accumulation, we detected the first synaptic dysfunction: an impairment of LTP in hippocampal CA3-CA1 synapses. Cognitively, at this time point, we observed a deficit in short-term memory. A reduction in basal synaptic strength and deficit in long-term associative spatial memory were only evident following 12 weeks of APPSw,Ind expression. Importantly, the plasticity impairment observed after 3 weeks of mature-onset APP expression is reversible. Together, these findings demonstrate important differences between developmental and mature-onset APP expression. Further research targeted at this early stage of synaptic dysfunction could help identify mechanisms to treat cognitive impairment in mild cognitive impairment (MCI) and early AD.

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Accepted/In Press date: 29 January 2019
e-pub ahead of print date: 22 February 2019

Identifiers

Local EPrints ID: 428257
URI: https://eprints.soton.ac.uk/id/eprint/428257
ISSN: 2051-5960
PURE UUID: 03fcd3de-fd5a-4192-966e-46abd591ca24
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682
ORCID for Katrin Deinhardt: ORCID iD orcid.org/0000-0002-6473-5298
ORCID for Mariana Vargas-Caballero: ORCID iD orcid.org/0000-0003-2326-4001

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Date deposited: 19 Feb 2019 17:30
Last modified: 10 Sep 2019 04:01

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Contributors

Author: Sarmi Sri
Author: Chrysia-Maria Pegasiou
Author: Chantal-Abbigail Cave
Author: Katie Hough
Author: Natalie Wood
Author: David Bannerman
Author: Victor Perry

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