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.
Highlights
Alzheimer’s disease is a neurodegenerative disease characterized by cognitive alterations, cerebral atrophy [1] and neuropathological lesions including neuronal loss [2], accumulation of misfolded and aggregated βamyloid peptide and tau proteins [3]
All brain samples were negative for presence of Prion proteins assessed by western blotting (Additional file 4: Figure S3)
This study demonstrated that inoculation of Alzheimer’s disease brain homogenates in middle-aged mouse lemurs induces alterations of long term memory and progressive loss of learning ability, modifications of neuronal activity detected by EEG, widespread and progressive cerebral atrophy, and neuronal loss in the hippocampus and entorhinal cortex
Summary
Alzheimer’s disease is a neurodegenerative disease characterized by cognitive alterations, cerebral atrophy [1] and neuropathological lesions including neuronal loss [2], accumulation of misfolded and aggregated βamyloid peptide and tau proteins [3]. Experimental induction (or acceleration) of β-amyloidosis or tauopathy has been described in rodents after intracerebral and even peripheral contamination with pathological Aβ or tau-bearing brain homogenates [7, 8]. Aged non-human primates can naturally develop β-amyloid lesions [10] and a longterm study in marmosets demonstrated induction of sparse β-amyloidosis 3.5 to 7 years post-inoculation, but there was no evidence of cognitive decline, neurodegeneration, functional Alzheimer’s disease hallmarks, or other clinical signs [11]. This calls for additional clinical analysis in primates after inoculation with Alzheimer’s disease brain homogenates
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
