Emergence of synaptic and cognitive impairment in a mature-onset APP mouse model of Alzheimer\u2019s disease

Sarmi Sri,Diego Gomez-Nicola,Mariana Vargas-Caballero,Chantal Abbigail Cave,Katie Hough,Chrysia-Maria Pegasiou,Katrin Deinhardt,David Bannerman,V Hugh Perry,Natalie Wood

doi:10.1186/s40478-019-0670-1

Sarmi Sri, Diego Gomez-Nicola + Show 8 more

Open Access

https://doi.org/10.1186/s40478-019-0670-1

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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/ Aβ 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, PLoS Med 2:e355, 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 Aβ-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 Aβ 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.

Highlights

Direct evidence from studies of the human brain suggests that hippocampal shrinkage [24] and synapse loss [18, 52] occur early in the pre-symptomatic and mild cognitive impairment (MCI) phases of Alzheimer’s disease (AD)
Transgenic amyloid precursor protein (APP) models allow for the analysis of chronic Aβ exposure and brain accumulation that could lead to a better understanding of the emergence and progression of cognitive impairment in AD
For example in the J20 line the PDGF promoter driven expression of APPSw,Ind starts at embryonic day 15 (E15) [51], in the Tg2576 line the PrP promoter driven expression of APPSw starts at E12 [1], and in the TASTPM line the Thy1 promoter driven expression of APPSw and Psen1 M146 V start at postnatal day 7 (P7) [12]

Summary

Introduction

Direct evidence from studies of the human brain suggests that hippocampal shrinkage [24] and synapse loss [18, 52] occur early in the pre-symptomatic and MCI phases of AD. Intervention at these early stages is becoming increasingly attractive from a therapeutic point of view as there is the potential to remove disease triggers and halt neurodegeneration prior to overt memory loss [28]. Sri et al Acta Neuropathologica Communications (2019) 7:25 available AD mouse models express proteins with familial disease-causing mutations starting from embryonic or early postnatal development, and can be considered as developmental-onset models of AD. For example in the J20 line the PDGF promoter driven expression of APPSw,Ind starts at embryonic day 15 (E15) [51], in the Tg2576 line the PrP promoter driven expression of APPSw starts at E12 [1], and in the TASTPM line the Thy promoter driven expression of APPSw and Psen M146 V start at postnatal day 7 (P7) [12]

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