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Amyloid precursor protein deficiency does not attenuate amyloid-associated pathology in BRI-A[beta]42 mice

  • Author(s): Ku, Claire Carmen
  • et al.
Abstract

The amyloid cascade hypothesis states that altered processing of amyloid precursor protein (APP) leads to increased production of amyloid-beta 42 (A[beta]42). A previous study has shown that mice over-expressing human A[beta]42 develop amyloid deposits with age, but whether this process is attenuated in APP deficient mice is unknown. We characterized amyloid-associated pathology in young (3-6 month) and old-age (12-15 month) BRI-A[beta]42 mice that overexpress A[beta]42 in the presence or absence of endogenous APP. 6E10 immunostaining and Thioflavin S staining revealed that old-age BRI-A[beta]42; APP mice developed significant levels of amyloid deposits in the hippocampus, but APP deficiency did not attenuate the levels of amyloid burden. Using an A[beta]42 sandwich ELISA, we found that BRI-A[beta]42; APP mice expressed soluble and insoluble A[beta]42 in the hemibrain. Soluble A[beta]42 levels were maintained throughout age, but old- age BRI-A[beta]42; APP mice produced 7 to 15 fold higher levels of insoluble A[beta]42 than the young-age group. Previous groups have demonstrated that A[beta] and APP can mediate neurotoxicity in vitro, but whether this interaction also contributes to synaptic damage in vivo is unknown. We tested whether APP is essential for A[beta]- induced synaptic damage in vivo by assessing the levels of two synaptic proteins in BRI-A[beta]42; APP mice : synaptophysin and PSD-95. Using western blotting, we found that there was no change in synaptic protein levels in BRI -A[beta]42; APP mice, so we did not find an APP-dependent effect on synaptic damage. Taken together, these results show that absence of APP does not mediate amyloid- associated pathology in BRI-A[beta]42; APP mice

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