Abstract
Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer’s disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches.Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.
Highlights
Aggregation of β-amyloid (Aβ) is a key pathological event in Alzheimer’s disease (AD) [14]
Absence of murine amyloid precursor protein (APP) promotes deposition of human β-amyloid Brain sections of mAPP0/0 and mAPP+/+ mice were immunostained for human Aβ to screen for qualitative and quantitative differences in cortical amyloidosis
The lack of endogenous mAPP resulted in accelerated deposition and, increased number of senile plaques and higher levels of aggregated human Aβ (hAβ)
Summary
Aggregation of β-amyloid (Aβ) is a key pathological event in Alzheimer’s disease (AD) [14]. While an increased production and/or aggregation propensity is triggering the accumulation of Aβ in familial forms of AD [32], sporadic cases of AD are characterised by impaired Aβ clearance [25]. The pathological events are initiated by overexpression of mutant human transgenes, namely the amyloid precursor protein (APP) and presenilin 1 or 2 (PS1/2) [29]. Steffen et al Acta Neuropathologica Communications (2017) 5:49 decisive role of transgenic models in basic, therapeutic and translational research, the impact of endogenous proteins should receive particular attention. To further elucidate the effect of mAPP in hAPP-transgenic models, we assessed the effect of its co-expression in an established transgenic model of cortical amyloidosis
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