Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease

Abstract

Alterations in amyloid precursor protein (APP) metabolism, calcium regulation, oxidative metabolism, and transduction systems have been implicated in Alzheimer's disease (AD). Limitations to the use of postmortem brain for examining molecular mechanisms underscore the need to develop a human tissue model representative of the pathophysiological processes that characterize AD. The use of peripheral tissues, particularly of cultured skin fibroblasts derived from AD patients, could complement studies of autopsy samples and provide a useful tool with which to investigate such dynamic processes as signal transduction systems, ionic homeostasis, oxidative metabolism, and APP processing. Peripheral cells as well as body fluids (i.e., plasma and CSF) could also provide peripheral biological markers for the diagnosis of AD. The criteria required for a definite diagnosis of AD presently include clinical criteria in association with histopathologic evidence obtained from biopsy or autopsy. Thus, the use of peripheral markers as a diagnostic tool, either to predict or at least to confirm a diagnosis, may be of great importance. Gasparini, L., Racchi, M., Binetti, G., Trabucchi, M., Solerte, S. B., Alkon, D., Etcheberrigaray, R., Gibson, G., Blass, J., Paoletti, R., Govoni, S. Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease. FASEB J. 12, 17–34 (1998)

Oxidative imbalance and cathepsin D changes as peripheral blood biomarkers of Alzheimer disease: A pilot study

“…The relationship between AD and APP pattern changes was also reported by Di Luca and coworkers, which hypothesized a pathogenic role for specific APP isoforms in periphery [17]. In this context, our data on APP seem to significantly extend previous studies on this argument [29], reinforcing the idea that the APP metabolism is altered not only in neuritic plaque, but also in the peripheral blood [20,13]. Furthermore, taking into account the results obtained by Basun et al [4] suggesting a plasmatic decrease of APP in AD patients, we cannot rule out the possibility that the absorption of APP by the platelets could contribute to this phenomenon.…”

Differential involvement of protein kinase C alpha and epsilon in the regulated secretion of soluble amyloid precursor protein

“…It is known that among multiple signal transduction molecules, different isoforms of PKC may be involved and can specifically contribute to the complex regulation of APP metabolism. Many of the signal transduction mechanisms, neurotransmitter receptors and other receptor ligands involved in APP processing regulation, have been described as defective in AD [29] and in some cases these defects have been associated with aberrant APP metabolism [26,[30][31][32]. PKC was one of the first signal transduction-related molecules to be implicated in the regulation of APP metabolism [2,3] suggesting, in particular, that the nonamyloidogenic a-secretase pathway is activated by PKC.…”

“…PKC was one of the first signal transduction-related molecules to be implicated in the regulation of APP metabolism [2,3] suggesting, in particular, that the nonamyloidogenic a-secretase pathway is activated by PKC. This simplification may not reflect the full complexity of the system, yet it is interesting to note that defective PKC is one of the most consistent findings in AD brain and peripheral tissues [29,33]. In fibroblasts from AD patients defective APP metabolism is paralleled by a specific downregulation of PKCa [26].…”

Amyloid in skin and brain: What′s the link?

“…Interestingly, presenilin-1 is also involved in epidermal growth factor receptor (EGFR) turnover, and it has been proven that partial loss of presenilin-1 expression may lead to seborrhoic keratoses and inflammatory skin diseases (81,82). In fact, there are numerous findings of altered skin physiology in patients suffering from AD (83)(84)(85)(86)(87)(88)(89)(90)(91)(92), some of which are already used for diagnostic or investigational purposes ( Fig. 1) (93)(94)(95)(96).…”