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

Amyloidogenic processing of β-amyloid precursor protein (APP) leading to Aβ accumulation is critical in Alzheimer’s disease (AD). Aβ 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 grow...

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Veröffentlicht in:Neurochemistry international 2003-08, Vol.43 (3), p.225-233
Hauptverfasser: Chauhan, N.B, Siegel, G.J
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Siegel, G.J
description Amyloidogenic processing of β-amyloid precursor protein (APP) leading to Aβ accumulation is critical in Alzheimer’s disease (AD). Aβ 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
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Aβ 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&lt;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 sAPPα, and 21-fold increases in Aβ40/42. PPF increased NGF-mRNA by 20% and sAPPα by 42% while decreasing Aβ40/42 by 45/48%, with no effect on p75-mRNA in Tg animals. ALCAR increased p75-mRNA by 16% and decreased Aβ40/42 by 46/26% with no significant effect on sAPPα or NGF-mRNA in Tg animals. The results indicate that NGF expression is reduced early in the Tg brain, that this reduction potentiates further Aβ formation in a vicious cycle, and that inducing NGF shifts the balance toward secretory processing of APP. 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Aβ 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&lt;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 sAPPα, and 21-fold increases in Aβ40/42. PPF increased NGF-mRNA by 20% and sAPPα by 42% while decreasing Aβ40/42 by 45/48%, with no effect on p75-mRNA in Tg animals. ALCAR increased p75-mRNA by 16% and decreased Aβ40/42 by 46/26% with no significant effect on sAPPα or NGF-mRNA in Tg animals. 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Aβ 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&lt;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 sAPPα, and 21-fold increases in Aβ40/42. PPF increased NGF-mRNA by 20% and sAPPα by 42% while decreasing Aβ40/42 by 45/48%, with no effect on p75-mRNA in Tg animals. ALCAR increased p75-mRNA by 16% and decreased Aβ40/42 by 46/26% with no significant effect on sAPPα or NGF-mRNA in Tg animals. The results indicate that NGF expression is reduced early in the Tg brain, that this reduction potentiates further Aβ formation in a vicious cycle, and that inducing NGF shifts the balance toward secretory processing of APP. To a lesser extent, p75 decreases Aβ peptides, possibly via peptidases since sAPPα level is not changed.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>12689602</pmid><doi>10.1016/S0197-0186(03)00006-8</doi><tpages>9</tpages></addata></record>
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ispartof Neurochemistry international, 2003-08, Vol.43 (3), p.225-233
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subjects Acetylcarnitine
Acetylcarnitine - physiology
Alzheimer’s disease
Amyloid
Amyloid beta-Protein Precursor - metabolism
Amyloid beta-Protein Precursor - physiology
Animals
APP processing
Base Sequence
Biological and medical sciences
Brain - metabolism
cRTPCR
DNA Primers
ELISA
Enzyme-Linked Immunosorbent Assay
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation - physiology
Mice
Mice, Transgenic
Nerve Growth Factor - genetics
Polymerase Chain Reaction
propentofylline
Protein Processing, Post-Translational
Receptor, Nerve Growth Factor
Receptors, Nerve Growth Factor - genetics
RNA, Messenger - genetics
Septohippocampal
title Effect of PPF and ALCAR on the Induction of NGF- and p75-mRNA and on APP processing in Tg2576 brain
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