Abstract
Amyloid-β (Aβ) pathology transmission has been described in patients following iatrogenic exposure to compounds contaminated with Aβ proteins. It can induce cerebral Aβ angiopathy resulting in brain hemorrhages and devastating clinical impacts. Iatrogenic transmission of tau pathology is also suspected but not experimentally proven. In both scenarios, lesions were detected several decades after the putatively triggering medico-surgical act. There is however little information regarding the cognitive repercussions in individuals who do not develop cerebral hemorrhages. In the current study, we inoculated the posterior cingulate cortex and underlying corpus callosum of young adult primates (Microcebus murinus) with either Alzheimer’s disease or control brain extracts. This led to widespread Aβ and tau pathologies in all of the Alzheimer-inoculated animals following a 21-month-long incubation period (n = 12) whereas none of the control brain extract-inoculated animals developed such lesions (n = 6). Aβ deposition affected almost all cortical regions. Tau pathology was also detected in Aβ-deposit-free regions distant from the inoculation sites (e.g. in the entorhinal cortex), while some regions adjacent, but not connected, to the inoculation sites were spared (e.g. the occipital cortex). Alzheimer-inoculated animals developed cognitive deficits and cerebral atrophy compared to controls. These pathologies were induced using two different batches of Alzheimer brain extracts. This is the first experimental demonstration that tau can be transmitted by human brain extracts inoculations in a primate. We also showed for the first time that the transmission of widespread Aβ and tau pathologies can be associated with cognitive decline. Our results thus reinforce the need to organize a systematic monitoring of individuals who underwent procedures associated with a risk of Aβ and tau iatrogenic transmission. They also provide support for Alzheimer brain-inoculated primates as relevant models of Alzheimer pathology.
Highlights
Prion diseases can occur after iatrogenic transmission of misfolded prion proteins
For the first time in a primate, we induced widespread Aβ and tau pathologies along with cognitive impairments and cerebral atrophy following the focal inoculation of Alzheimer’s disease (AD) brain extracts in the cingulate cortex and underlying corpus callosum
Aβ deposits were detected using specific antibodies as well as Thioflavin S staining. They were observed close to the inoculation site and in almost all cortical regions as well as in the hippocampus, suggesting their efficient spreading within the whole brain
Summary
Prion diseases can occur after iatrogenic transmission of misfolded prion proteins. The aberrant proteins propagate by imposing their abnormal conformation on theLam et al acta neuropathol commun (2021) 9:165 contaminated with Aβ [9, 21]. Prion diseases can occur after iatrogenic transmission of misfolded prion proteins. The pathology occurred as Aβ plaques in the brain as well as vascular Aβ pathology that could be associated with fatal cerebral hemorrhages. Observational evidence of tau iatrogenic transmission is not as widely reported as for Aβ. A recent article detected tau lesions after incubation periods exceeding three decades in patients with iatrogenic Aβ pathology [16]. Because of the long incubation time in humans, it remains difficult to determine whether the Aβ and tau pathologies were really transmitted. Another critical question is whether, in the absence of severe cerebral hemorrhages, Aβ and/or tau transmissions can lead to cognitive impairments
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