Induction of amyloid-\u03b2 deposits from serially transmitted, histologically silent, A\u03b2 seeds issued from human brains

Anne-Sophie Hérard,Charlotte Gary,Suzanne Lam,Susana Boluda,Marc Dhenain,Fanny Petit,Martine Guillermier,Clément M Garin

doi:10.1186/s40478-020-01081-7

Abstract

In humans, iatrogenic transmission of cerebral amyloid-β (Aβ)-amyloidosis is suspected following inoculation of pituitary-derived hormones or dural grafts presumably contaminated with Aβ proteins as well as after cerebral surgeries. Experimentally, intracerebral inoculation of brain homogenate extracts containing misfolded Aβ can seed Aβ deposition in transgenic mouse models of amyloidosis or in non-human primates. The transmission of cerebral Aβ is governed by the host and by the inoculated samples. It is critical to better characterize the propensities of different hosts to develop Aβ deposition after contamination by an Aβ-positive sample as well as to better assess which biological samples can transmit this lesion. Aβ precursor protein (huAPPwt) mice express humanized non-mutated forms of Aβ precursor protein and do not spontaneously develop Aβ or amyloid deposits. We found that inoculation of Aβ-positive brain extracts from Alzheimer patients in these mice leads to a sparse Aβ deposition close to the alveus 18 months post-inoculation. However, it does not induce cortical or hippocampal Aβ deposition. Secondary inoculation of apparently amyloid deposit-free hippocampal extracts from these huAPPwt mice to APPswe/PS1dE9 mouse models of amyloidosis enhanced Aβ deposition in the alveus 9 months post-inoculation. This suggests that Aβ seeds issued from human brain samples can persist in furtive forms in brain tissues while maintaining their ability to foster Aβ deposition in receptive hosts that overexpress endogenous Aβ. This work emphasizes the need for high-level preventive measures, especially in the context of neurosurgery, to prevent the risk of iatrogenic transmission of Aβ lesions from samples with sparse amyloid markers.

Highlights

Epidemiological data suggest that, in humans, iatrogenic cerebral Aβ-amyloidosis can be induced following administration of cadaver-sourced human growth hormone [3, 9] or dura mater graft [8] containing amyloid-β (Aβ) proteins as well as after cerebral surgeries potentially involving tools contaminated with Aβ [10]
We demonstrated that, 4 months after inoculation, A PPswe/ PS1dE9 mice inoculated with the same AD brain extracts display increased amyloid plaque deposition and higher level of biochemically detectable Aβ as compared to mice inoculated with a CTRL human brain extract [5]
AD-huAPPwt brains (a–b, arrows). 4G8 staining did not involve blood vessels as highlighted here in a mouse inoculated with AD-huAPPwt (h). 4G8-positive load (e) and the number of plaques per surface unit (f) were significantly increased in the region surrounding the alveus of AD-APPswe/PS1dE9 mice compared to the CTRL-APPswe/PS1dE9 (U = 1, p = 0.004 **, and U = 3, p = 0.015 *, respectively). g Amyloid load was not different in the hippocampus of AD-APPswe/PS1dE9 and CTRL-APPswe/PS1dE9 mice (U = 11, p = 0.3)

Summary

Introduction

Epidemiological data suggest that, in humans, iatrogenic cerebral Aβ-amyloidosis can be induced following administration of cadaver-sourced human growth hormone [3, 9] or dura mater graft [8] containing amyloid-β (Aβ) proteins as well as after cerebral surgeries potentially involving tools contaminated with Aβ [10]. We found that intra-hippocampal inoculation of human AD brain extracts to huAPPwt mice, a model that expresses humanized non-mutated forms of AβPP and does not spontaneously develop amyloid deposits, induces slight Aβ deposition in regions surrounding the alveus but not in other parts of the hippocampus or brain regions. This suggests that induction of cerebral Aβ deposition is low in models that have a low propensity to develop amyloid pathology. This suggests that the prevention of iatrogenic amyloid transmission from one patient to another does not rely solely on the amyloid status of the donors since samples with sparse Aβ lesions can induce pathology in a receptive host

Methods

Results

Conclusion