PubMed · 8931264
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A J Harmar, A D Ogilvie. 1996. Function and dysfunction in the nervous system.. https://doi.org/10.1016/s0166-2236(96)30014-3
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Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid beta peptide (Abeta) production are believed to play a major role in Alzheimer's disease (AD). Therefore, reducing Abeta production in the brain is a possible therapy for AD. Because AD pathology is fairly restricted to the CNS of humans, we have established human cerebral primary neuron cultures to investigate the metabolism of APP. In many cell lines and rodent primary neuron cultures, phorbol ester activation of protein kinase C (PKC) increases the release of the secreted large N-terminal fragment of amyloid precursor protein (sAPP) and decreases Abeta release (; ; ). In contrast, we find that PKC activation in human primary neurons increases the rate of sAPP release and the production of APP C-terminal fragments and 4 kDa Abeta. Our results indicate species- and cell type-specific regulation of APP metabolism. Therefore, our results curtail the use of PKC activators in controlling human brain Abeta levels.
In molecular neurobiology, perhaps no molecule has been as thoroughly examined as Alzheimer's beta-amyloid precursor protein (betaAPP). In the ten years since the cDNA encoding betaAPP was cloned, the protein has been the subject of unparalleled scrutiny on all levels. From molecular genetics and cellular biology to neuroanatomy and epidemiology, no scientific discipline has been left unexplored - and with good reason. beta-amyloid (Abeta) is the main constituent of the amyloidogenic plaques which are a primary pathological hallmark of Alzheimer's disease, and betaAPP is the protein from which Abeta is cleaved and released. Unraveling the molecular events underlying Abeta generation has been, and remains, of paramount importance to scientists in our field. In this review we will trace the progress that has been made in understanding the molecular and cellular basis of betaAPP trafficking and processing, or alternatively stated, the molecular basis for Abeta generation. Imperative to a complete understanding of Abeta generation is the delineation of its subcellular localization and the identification of proteins which play either direct or accessory roles in Abeta generation. We will focus on the regulation of betaAPP cleavage through diverse signal transduction mechanisms and discuss possible points of therapeutic intercession in what has been postulated to be a seminal molecular step in the cascade of events terminating in the onset of dementia, a loss of neurons, and tragically, eventual death from Alzheimer's disease.
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