Alzheimer’s disease (AD) currently afflicts 6.5 million Americans (5.1 million over the age of 65) and is projected to increase to between 11 and 16 million by 2050 (“2009 Alzheimer’s disease facts and figures,” 2009
). Over $4 billion in revenues are currently generated by the five US federal drug agency (FDA)–approved drugs: Aricept (Donepezil, Pfizer), Cognex (Tacrine, Parke–Davis), Razadyne (Galantamine, Ortho–McNeil–Janssen), Exelon (Rivastigmine, Novartis), and Namenda (Memantine, Forest). These current therapies for AD provide only mild, transient symptomatic relief. A significant unmet need exists for improved drugs, which are based on novel molecular targets that modify the underlying course and address the etiology of the disease. To design drugs for this end, the fundamental activities of molecules such as amyloid–β peptide (Aβ), Aβ precursor protein (AβPP), β–site AβPP–cleaving enzyme 1 (BACE1)—the β–secretase molecule, and presenilin–1 (PSEN1)—a necessary component of γ–secretase activity—must be elucidated. The Aβ peptide is of particular interest, as it is the center of the “amyloid cascade” hypothesis—the currently dominant model of AD etiology. In addition, understanding of normal Aβ clearance pathways, such as insulin degrading enzyme (IDE), is important for therapeutic use Aβ metabolism (Eckman and Eckman, 2005
The processing of AβPP into Aβ requires two enzymatic activities. AβPP is first cleaved by β–secretase, producing soluble AβPP and a cell–membrane bound fragment (Lahiri, et al., 2003
). This fragment is further cleaved by γ–secretase to produce Aβ and the AβPP intracellular domain (AICD). AICD has been shown to function in regulation of gene transcription (Konietzko, et al., 2010
), indicating an important non pathogenic role for γ–secretase. However, the Aβ generation is a minority AβPP processing pathway. The majority of AβPP is cleaved by α–secretase, a large molecule complex that includes members of the ADAM protein family (Asai, et al., 2003
). This pathway represents a neuroprotective route for AβPP processing (Kojro and Fahrenholz, 2005
), and encouraging the α–secretase pathway may be clinically productive (Fahrenholz, 2007
In “Signaling effect of amyloid–β42 on the processing of AβPP”, Tabaton et al present a model of Aβ function and portray it primarily as an extracellular signaling peptide that begins a cascade which regulates both β– and γ–secretase activity, thus regulating both steps of its own cleavage from the Aβ precursor protein, AβPP. Their review presents another emerging picture of the state of knowledge regarding both Aβ dysfunction and BACE1.
When summarizing the “normal” functions of Aβ, the authors stress a potential role as a signaling pathway partner to TrkA, MAPK, and JNK to the exclusion of most other potential functions. Similarities between Aβ and Notch are noted in the paper. The authors provide a more complete picture of Aβ dysfunction, highlighting its toxic and oxidative activities as individual subunits and oligomers, and its formation into amyloid plaque in AD brains. Each of these potential activities is of more than theoretical importance, since each lends itself to different therapeutic responses.