Exogenous induction of cerebral beta-amyloidosis in betaAPP-transgenic mice.
A key commonality of most age-related neurodegenerative diseases is the accumulation of aggregation-prone proteins in the brain. Except for the prionoses, the initiation and propagation of these proteopathies in vivo remains poorly understood. In a previous study, we found that the deposition of the amyloidogenic peptide Abeta can be induced by injection of dilute extracts of Alzheimeric neocortex into the brains of Tg2576 transgenic mice overexpressing the human beta-amyloid precursor protein. The present study was undertaken to assess the pathology after long-term (12 months) incubation, and to clarify the distinctive anatomical distribution of seeded Abeta-immunoreactivity. All mice were injected at 3 months of age; 5 months later, as expected, Abeta deposits were concentrated mostly in the injected hemisphere. After 12 months, abundant, transgene-derived Abeta deposits were present bilaterally in the forebrain, but plaque load was still clearly greater in the extract-injected hemisphere. There was also evidence of tau hyperphosphorylation in axons of the corpus callosum that had been injured by the injection, most prominently in transgenic mice, but also, to a lesser degree, in non-transgenic mice. Five months following injection of AD-extract, an isolated cluster of Abeta-immunoreactive microglia was sometimes evident in the ipsilateral entorhinal cortex; the strong innervation of the hippocampus by entorhinal cortical neurons suggests the possible spread of seeded pathology from the injection site via neuronal transport mechanisms. Finally, using India Ink to map the local dispersion of injectate, we found that Abeta induction is especially potent in places where the injectate is sequestered. The AD-seeding model can illuminate the emergence and spread of cerebral beta-amyloidosis and tau hyperphosphorylation, and thus could enhance our understanding of AD and its pathogenic commonalties with other cerebral proteopathies.
CNS Pharmacology, Pfizer Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. lary.walker@pfizer.com
Lary C
LC
Walker
Michael J
MJ
Callahan
Feng
F
Bian
Robert A
RA
Durham
Alex E
AE
Roher
William J
WJ
Lipinski
D016564:Amyloid beta-Protein Precursor / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*; D000686:Amyloidosis / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D003337:Corpus Callosum / Q000166:cytology; D018728:Entorhinal Cortex / Q000473:pathology; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor