Tissue-specific expression of three types of β-protein precursor mRNA: Enhancement of protease inhibitor-harboring types in Alzheimer's disease brain

P2X7 Receptor-mediated Scavenger Activity of Mononuclear Phagocytes toward Non-opsonized Particles and Apoptotic Cells Is Inhibited by Serum Glycoproteins but Remains Active in Cerebrospinal Fluid

“…Similar to CP, APP has recently been found to have both ferroxidase (28) and amine oxidase activity (29); however, it is not known if these enzymatic activities are modified by the presence of P2X7. APP is transcribed into a number of isoforms, with APP695 being the predominant form expressed in neuronal tissue, whereas isoforms APP751 and APP770 (containing the Kunitz protease inhibitor domain, respectively, without and with the Ox-2 domain) are widely expressed in non-neuronal cells (30). All isoforms are further modified through proteolytic cleavage, yielding major products including soluble APP␣ and APP␤ present in most biological fluids including serum as well as the A␤ peptides that make up the major components of amyloid deposition in cardiovascular and brain tissue.…”

Variability of .BETA.-Amyloid Protein Deposited Lesions in Down's Syndrome Brains.

“…Taken together with these hypotheses, in considering the pathogenesis of AD, it is very important to clarify the cellular source of /3-APP and the processing of this precursor protein into insoluble amyloid fibrils. Three main isoforms of /3-APP (/3-APP695, 751 and 770) produced by alternatively spliced mRNAs from a single gene have been identified, and CNS neurons have particularly high levels of l-APP695 expression, whereas in peripheral tissues, f3-APPs751 and 770 are the predominant forms (Tanaka et al 1989;Golde et al 1990). Moreover, soluble secretory derivatives of these f3-APP molecules have been detected in serum (Bush et al 1992), cerebrospinal fluid (Kennedy et al 1992), brain parenchyma (Kametani et al 1993) and the growth medium of several cell cultures (Andersson et al 1991).…”

P1‐251: The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a β‐secretase dependent pathway

“…However, it has been reported previously that in both human brain and cerebrospinal fluid, an antibody to the initial part of the A␤ sequence recognized only the soluble forms of APP that were also reactive to antibodies against the KPI domain, leading to the suggestion that A␤ may be generated in vivo in humans specifically from the non-KPI 695 isoform (40,41). The increased expression of the KPI-containing isoforms of APP in the brain of AD patients (7)(8)(9) and following excitotoxic, ischemic, or oxidative insult (10 -12) may thus reflect a neuroprotective process to reduce the production of A␤, particularly the more amyloidogenic A␤ , from the 695 isoform.…”

“…In the brain, APP 695 is expressed at high levels, and the APP 751/770 isoforms are expressed at significantly lower levels, although there are regional differences, and it has been suggested that the balance between the KPI-and non-KPI-containing isoforms may be an important factor influencing A␤ deposition (6). In the AD brain (7)(8)(9) and in response to N-methyl-Daspartate (NMDA) receptor stimulation (10,11), there is an increase in the proportion of KPI-to non-KPI-containing isoforms of APP. This has led to the suggestion that the KPIcontaining isoforms of APP can exert important neuroprotective functions, and thus their up-regulation in the AD brain or in response to excitotoxic insult may be to protect against further neuronal loss (12, 13).…”