Amyloid Beta Hypothesis: Attention to β- and γ-Secretase Modulators

The amyloid cascade hypothesis poses one possible explanation for the onset and progres- sion of Alzheimer’s disease (AD). With this respect, neurotoxic effect is attributed to soluble and diffusive amyloid-β (Aβ) oligomers. Aβ peptides are produced by proteolytic cleavage of the hydrophobic transmembrane portion of the amyloid precursor protein (APP) by suc-cessive action of β- and γ-secretases. Aβ peptides are generated in several isoforms, out of which the most pronounced are Aβ40 and Aβ42 being the major constituents of amyloid plaques found in AD patients’ brains. Since the indisputable evidence pointed out to Aβ oligomers as toxic agents, several pathways to modulate or control the aggregation have been inspected . Given all these aspects, inhibitors of the β- and γ-secretases have gained the most attention. This chapter presents amyloid cascade hypothesis with current progress in the development of β- and γ-secretase modulators to counteract the Aβ burden. BACE-2 knockout (−/−) mice showed the same phenotype. Double-knockout mice, that is, mice with deactivated genes for BACE-1 (−/−) as well as for BACE-2 (−/−), are not phenotypically very different from mice without the gene for the BACE-1, with the exception of an increased num ber of dying mice freshly after birth. The results of this study therefore assume that nonselective inhibitors of both subtypes of the enzyme BACE may be well tolerated at least from the perspec tive of the inhibition of BACE-2. The latest research has shown that BACE-2 is expressed in the pancreatic β cells and BACE-2 knockout mice exhibit an improved glycemic regulation due to the increased production of insulin. These findings imply the possible use of BACE-2 inhibitors for the treatment of diabetes mellitus of type 2 [ 15].