Time course of the development of Alzheimer-like pathology in the doubly transgenic PS1+APP mouse

Marcia N. Gordon, Leigh A. Holcomb, Paul T. Jantzen, Giovanni DiCarlo, Donna Wilcock, Kristal W. Boyett, Karen Connor, Jason Melachrino, James P. O'Callaghan, Dave Morgan

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

Doubly transgenic mice expressing both a mutated amyloid precursor protein and a mutated presenilin-1 protein accumulate Aβ deposits as they age. The early Aβ deposits were found to be primarily composed of fibrillar Aβ and resembled compact amyloid plaques. As the mice aged, nonfibrillar Aβ deposits increased in number and spread to regions not typically associated with amyloid plaques in Alzheimer's disease. The fibrillar, amyloid-containing deposits remained restricted to cortical and hippocampal structures and did not increase substantially beyond the 12-month time point. Even at early time points, the fibrillar deposits were associated with dystrophic neurites and activated astrocytes expressing elevated levels of glial fibrillary acidic protein. Microglia similarly demonstrated increased staining for complement receptor-3 in the vicinity of Aβ deposits at early time points. However, when MHC-II staining was used to assess the degree of microglial activation, full activation was not detected until mice were 12 months or older. Overall, the regional pattern of Aβ staining resembles that found in Alzheimer disease; however, a progression from diffuse Aβ to more compact amyloid deposits is not observed in the mouse model. It is noted that the activation of microglia at 12 months is coincident with the apparent stabilization of fibrillar Aβ deposits, raising the possibility that activated microglia might clear fibrillar Aβ deposits at a rate similar to their rate of formation, thereby establishing a relatively steady-state level of amyloid-containing deposits.

Original languageEnglish
Pages (from-to)183-195
Number of pages13
JournalExperimental Neurology
Volume173
Issue number2
DOIs
StatePublished - 2002

Bibliographical note

Funding Information:
This work was supported by AG 15490 (M.N.G.), AG 18478 (D.M.), and the Benjamin Alzheimer trust (D.M.). We thank Karen Hsiao-Ashe for providing the APP mice and Karen Duff for providing the PS1 mice and Paul Gottschall for the AβTOT antiserum.

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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