Format

Send to

Choose Destination
Acta Neuropathol Commun. 2019 Sep 4;7(1):126. doi: 10.1186/s40478-019-0771-x.

Encephalopathy induced by Alzheimer brain inoculation in a non-human primate.

Author information

1
Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay UMR 9199, Laboratoire des Maladies Neurodégénératives, 18 Route du Panorama, F-92265, Fontenay-aux-Roses, France.
2
Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut François Jacob, MIRCen, 18 Route du Panorama, F-92265, Fontenay-aux-Roses, France.
3
University of Wisconsin Oshkosh, 800 Algoma Boulevard, Oshkosh, WI, 54901, USA.
4
Wolfson Brain Imaging Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
5
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
6
LabEx DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease), Université de Lille, Inserm, CHU-Lille, UMR-S1172, Alzheimer & Tauopathies, Rue Polonovski, 59045, Lille, France.
7
UMR7179 CNRS-MNHN, MECADEV (Adaptive Mechanisms and Evolution), 1 Avenue du Petit Château, 91800, Brunoy, France.
8
Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut François Jacob, SEPIA, Université Paris-Saclay, 18 Route du Panorama, F-92265, Fontenay-aux-Roses, France.
9
Laboratoire de Psychopathologie et de Neuropsychologie, EA, 2027, Université Paris 8, St-Denis, France.
10
Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay UMR 9199, Laboratoire des Maladies Neurodégénératives, 18 Route du Panorama, F-92265, Fontenay-aux-Roses, France. marc.dhenain@cea.fr.
11
Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut François Jacob, MIRCen, 18 Route du Panorama, F-92265, Fontenay-aux-Roses, France. marc.dhenain@cea.fr.

Abstract

Alzheimer's disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated β-amyloid peptides (Aβ) and tau proteins. Iatrogenic induction of Aβ is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aβ. Induction of Aβ and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer's disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aβ or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer's disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes.

KEYWORDS:

Alzheimer’s disease; Cerebral atrophy; Cognitive impairment; Microcebus murinus; Mouse; Neurodegenerative disease; Neuronal function; Prion; Tau pathology; β-Amyloid pathology

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center