Evidence for Seeding of β-Amyloid by Intracerebral Infusion of Alzheimer Brain Extracts in β-Amyloid Precursor Protein-Transgenic Mice

Abstract

Many neurodegenerative diseases are associated with the abnormal sequestration of disease-specific proteins in the brain, but the events that initiate this process remain unclear. To determine whether the deposition of the beta-amyloid peptide (Abeta), a key pathological feature of Alzheimer's disease (AD), can be induced in vivo, we infused dilute supernatants of autopsy-derived neocortical homogenates from Alzheimer's patients unilaterally into the hippocampus and neocortex of 3-month-old beta-amyloid precursor protein (betaAPP)-transgenic mice. Up to 4 weeks after the infusion there was no Abeta-deposition in the brain; however, after 5 months, the AD-tissue-injected hemisphere of the transgenic mice had developed profuse Abeta-immunoreactive senile plaques and vascular deposits, some of which were birefringent with Congo Red. There was limited deposition of diffuse Abeta also in the brains of betaAPP-transgenic mice infused with tissue from an age-matched, non-AD brain with mild beta-amyloidosis, but none in mice receiving extract from a young control case. Abeta deposits also were not found in either vehicle-injected or uninjected transgenic mice or in any nontransgenic mice. The results show that cerebral beta-amyloid can be seeded in vivo by a single inoculation of dilute AD brain extract, demonstrating a key pathogenic commonality between beta-amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo beta-amyloidogenesis in the brain and may yield a more authentic animal model of Alzheimer's disease and other neurodegenerative disorders.

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

“…Alternatively, transient exposure to Ab may trigger a cascade of events that persist for long periods. For example, intracerebral injections of either AD brain Ab or soluble Ab from amyloid precursor proteintransgenic (APP) transgenic mouse brain have been reported to act as seeds for the aggregation of endogenous Ab in APP transgenic, but not wild-type, mice, several months after innoculation [56,57]. It will be of interest to determine how much longer, beyond the week we report here, that the synaptic plasticity disrupting action of soluble Ab from AD brain persists in wild-type rats.…”

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…This induced widespread senile plaques that were found as far as the contralateral hemisphere. In contrast, brain homogenate that lacked Aβ pathology did not induce plaque deposition [15,16]. Brain lysate from a transgenic mouse model of AD also induced Aβ pathology in APP-expressing mice, demonstrating that the toxic agent was not specific to the human brain [15].…”

On the issue of transmissibility of Alzheimer disease

“…Induction of cerebral amyloidoses appears to be possible by intracerebral "seeding" as has been demonstrated by Kane et al, who injected brain homogenate of AD patients into transgenic mice, which in return developed profuse Aβ plaque formations 23 or by DeGiorgio, who implanted tissue samples from AD patients' meninges or skin into mice cortices. 24 These mice developed plaques consisting of APP, Aβ, cathepsin D, apolipoprotein E and ubiquitin.…”