Transmission of amyloid-beta and tau pathologies is associated with cognitive impairments in a primate

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.

LRP1 and SORL1 regulate tau internalization and degradation and enhance tau seeding

ABSTRACTThe identification of the apoE receptor, LRP1, as an endocytic receptor for tau raises several questions about LRP1s’ role in tauopathies. Is internalized tau, like other LRP1 ligands, delivered to lysosomes for degradation? Does LRP1 internalize pathological tau leading to cytosolic seeding? Do other, related receptors participate in these processes? We confirm that LRP1 rapidly internalizes tau, leading to efficient lysosomal degradation. Employing brain homogenates from human Alzheimer brain, we find that LRP1 also mediates cytosolic tau seeding. We additionally found that another apoE receptor, SORL1, a gene implicated in AD risk, also mediates tau endocytosis, degradation, and release into the cytoplasm of seed competent species. These data suggest a role for these apoE receptors in tau uptake, as well as the competing processes of degradation and release to the cytoplasm. The balance of these processes may be fundamental to spread of neuropathology across the brain in Alzheimer disease.