Effect of PPF and ALCAR on the induction of NGF- and p75-mRNA and on APP processing in Tg2576 brain.

Amyloidogenic processing of beta-amyloid precursor protein (APP) leading to Abeta accumulation is critical in Alzheimer's disease (AD). Abeta leads to pre-synaptic molecular changes in hippocampus of the AD mutant transgenic mouse model Tg2576 prior to plaque formation. Since NGF is critical to neuronal growth and is involved in regulating APP processing, we tested the hypothesis that NGF expression is altered early in this model of AD. We measured APP products and mRNAs for NGF and its low-affinity receptor p75 in 10-month-old Tg2576 whole brain after dietary propentofylline (PPF) or acetyl-L-carnitine (ALCAR) for 4 weeks to induce NGF- or p75-expression, respectively. The results (all P<0.0002) show that compared to wild-type or littermate controls, the transgene leads to decreases of 44% in NGF-mRNA, 25% in p75-mRNA, 64% in sAPPalpha, and 21-fold increases in Abeta40/42. PPF increased NGF-mRNA by 20% and sAPPalpha by 42% while decreasing Abeta40/42 by 45/48%, with no effect on p75-mRNA in Tg animals. ALCAR increased p75-mRNA by 16% and decreased Abeta40/42 by 46/26% with no significant effect on sAPPalpha or NGF-mRNA in Tg animals. The results indicate that NGF expression is reduced early in the Tg brain, that this reduction potentiates further Abeta formation in a vicious cycle, and that inducing NGF shifts the balance toward secretory processing of APP. To a lesser extent, p75 decreases Abeta peptides, possibly via peptidases since sAPPalpha level is not changed.