Treatment Strategies Targeting Amyloid  -Protein

Abstract

With the advent of the key discovery in the mid-1980s that the amyloid b-protein (Ab) is the core constituent of the amyloid plaque pathology found in Alzheimer disease (AD), an intensive effort has been underway to attempt to mitigate its role in the hope of treating the disease. This effort fully matured when it was clarified that the Ab is a normal product of cleavage of the amyloid precursor protein, and well-defined proteases for this process were identified. Further therapeutic options have been developed around the concept of anti-Ab aggregation inhibitors and the surprising finding that immunization with Ab itself leads to reduction of pathology in animal models of the disease. Here we review the progress in this field toward the goal of targeting Ab for treatment and prevention of AD and identify some of the major challenges for the future of this area of medicine.

Trafficking and Proteolytic Processing of APP

“…3): one leading predominantly to Ab42 generation (starting with the 1-cleavage after amino acid 48 and followed by cleavages after amino acids 45 and 42); and the other leading predominantly to Ab40 (starting with the 1-cleavage after amino acid 49 and followed by cleavages after amino acids 46 and 43). As discussed in Schenk et al (2011), these cleavages may be therapeutically modulated to selectively prevent Ab42 generation.…”

“…The amyloidogenic and the anti-amyloidogenic processing pathways compete with each other at least in some subcellular loci, since enhancing a-secretase activity in animal models of Alzheimer disease (AD) or in cultured cells can significantly lower Ab generation and even amyloid plaque formation (Nitsch et al 1992;Postina et al 2004). A number of familial Alzheimer disease (FAD)-associated mutations have been found within and around the Ab domain (Chartier-Harlin et al 1991;Selkoe 2001; discussed in detail in Schenk et al 2011). These mutations accelerate disease progression via diverse mechanisms.…”

“…This is an important issue, because accumulation of such CTFs may cause additional, poorly understood toxic effects. Progress has been made toward the generation of BACE1 inhibitors, and clinical studies are on the way (Citron 2004;Schenk et al 2011). However, one must be aware that such an approach also inhibits the physiological function of BACE1.…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…However, in phase III trials, cognitive assessments and MRI measures were unaffected in response to the treatment, the reasons for which remain unclear (Aisen et al 2011). The other therapy, ELND005 (scyllo-inositol) was well tolerated in humans at lower doses, but as yet the therapy's effect on Aβ aggregation and on AD patients remains to be determined (Salloway et al 2011;Schenk et al 2012). …”

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

“…Upon γ-secretase cleavage, Aβ is liberated and then found in extracellular fluids such as plasma or cerebrospinal fluid . A large number of EOFAD -associated APP mutations have been found within and around the Aβ domain (Chartier-Harlin et al, 1991;Schenk et al, 2012;Selkoe, 2001) but appear to accelerate disease progression via diverse mechanisms (Citron M, 1992;Mullan, 1992;Nilsberth et al, 2001;Shoji et al, 1992;Suzuki et al, 1994).…”