In both trisomy 21 and rare cases of triplication of amyloid precursor protein (APP)
Alzheimer's disease (AD) pathological changes are believed to be secondary to increased
expression of APP. We hypothesized that sporadic AD may also be associated with changes
in transcription of APP or its metabolic partners. To address this issue, temporal
neocortex of 27 AD and 21 non-demented control brains was examined to assess mRNA
levels of APP isoforms (total APP, APP containing the Kunitz protease inhibitor domain
[APP-KPI] and APP770) and APP metabolic enzymatic partners (the APP cleaving enzymes
beta-secretase [BACE] and presenilin-1 [PS-1], and putative clearance molecules, low-density
lipoprotein receptor protein [LRP] and apolipoprotein E [apoE]). Furthermore, we evaluated
how changes in APP at the mRNA level affect the amount of Tris buffer extractable
APP protein and Abeta40 and 42 peptides in AD and control brains. As assessed by quantitative
PCR, APP-KPI (p=0.007), APP770 (p=0.004), PS-1 (p=0.004), LRP (p=0.003), apoE (p=0.0002)
and GFAP (p<0.0001) mRNA levels all increased in AD, and there was a shift from APP695
(a neuronal isoform) towards KPI containing isoforms that are present in glia as well.
APP-KPI mRNA levels correlated with soluble APPalpha-KPI protein (sAPPalpha-KPI) levels
measured by ELISA (tau=0.33, p=0.015 by Kendall's rank correlation); in turn, soluble
APPalpha-KPI protein levels positively correlated with Tris-extractable, soluble Abeta40
(p=0.046) and 42 levels (p=0.007). The ratio of soluble APPalpha-KPI protein levels
to total APP protein increased in AD, and also correlated with GFAP protein levels
in AD. These results suggest that altered transcription of APP in AD is proportionately
associated with Abeta peptide, may occur in the context of gliosis, and may contribute
to Abeta deposition in sporadic AD.