Activation of α-secretase activity to increase non-amyloidogenic processing of APP is definitely one of the hottest topics among the current experimental approaches in AD. Undoubtedly, it also constitutes a major challenge (but are there minor ones in AD?), because inhibition, not activation, is the natural pharmacological reflex.

This paper offers another handle on the problem, via the PACAP peptide and its PAC1, G-protein coupled receptor that activates ADAM10. This complements the previous identification of ADAM10 as the major α-secretase activity acting on APP in vivo (Postina et al., 2004). The activation of ADAM10 by the PACAP-PAC1 signaling cascade, although not yet understood in molecular terms, appears now ready to be tested in vivo in a transgenic model. Thereby several other problems can be faced, given that PACAP is a peptide and therefore not the best-suited in vivo ligand, and in terms of triggering pharma's interest. Proof-of-principle in vivo is nevertheless needed to upgrade the PACAP-PAC1 switch to the status of "most exciting" therapeutic target.

References:
Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest. 2004 May;113(10):1456-64. Erratum in: J Clin Invest. 2004 Aug;114(4):598. Abstract

View all comments by Fred Van Leuven

This group of German and Belgian investigators has produced what is apparently the first evidence that a member of the ADAM family of proteases functions as an alpha secretase for the beta amyloid precursor protein substrate in vivo. An attractive feature of the experimental approach was the evaluation of the impacts of different degrees of overexpression of the protease. A dominant negative construct was also employed. In crosses with APP V717I transgenic mice, morphological and functional studies demonstrated clear evidence of a protective effect of moderate overexpression of ADAM10. Enhanced production of neuroprotective APPsalpha and decreased levels of beta amyloid peptides were associated with such moderate overexpression. The results provide strong rationales for the further development of clinical interventions based upon enhancements of such alpha secretase activities. Such interventions will have to hit upon an appropriate level of enhancement, as we can assume that other products of APP processing, including beta amyloid peptides, have physiological functions that also...  Read more

This group of German and Belgian investigators has produced what is apparently the first evidence that a member of the ADAM family of proteases functions as an alpha secretase for the beta amyloid precursor protein substrate in vivo. An attractive feature of the experimental approach was the evaluation of the impacts of different degrees of overexpression of the protease. A dominant negative construct was also employed. In crosses with APP V717I transgenic mice, morphological and functional studies demonstrated clear evidence of a protective effect of moderate overexpression of ADAM10. Enhanced production of neuroprotective APPsalpha and decreased levels of beta amyloid peptides were associated with such moderate overexpression. The results provide strong rationales for the further development of clinical interventions based upon enhancements of such alpha secretase activities. Such interventions will have to hit upon an appropriate level of enhancement, as we can assume that other products of APP processing, including beta amyloid peptides, have physiological functions that also require optimal concentrations.

View all comments by George M. Martin

One effective way to enhance adequate functioning of the α-secretase, which is zinc-based, may be to maintain normal zinc serum levels. Tully from the Nun Study found that normal fasting serum zinc, measured one year before death, showed moderate to strong negative correlation with senile plaques in seven brain regions. The Age-Related Eye Disease Study found that supplements of 80 mg/day of zinc, a high dosage over seven years, appeared to prevent cognitive impairment in persons with a mean of 75 years of age. Potocnik found a modest zinc dose of 30 mg/day to postpone AD disease progression by 7 to 9 months.

References:
Tully CL, Snowdon DA, Markesbery WR. Serum zinc, senile plaques, and neurofibrillary tangles: findings from the Nun Study. Neuroreport. 1995 Nov 13;6(16):2105-8. Abstract

Yaffe K, Clemons TE, McBee WL, Lindblad AS; Age-Related Eye Disease Study Research Group. Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology. 2004 Nov 9;63(9):1705-7.   Read more

One effective way to enhance adequate functioning of the α-secretase, which is zinc-based, may be to maintain normal zinc serum levels. Tully from the Nun Study found that normal fasting serum zinc, measured one year before death, showed moderate to strong negative correlation with senile plaques in seven brain regions. The Age-Related Eye Disease Study found that supplements of 80 mg/day of zinc, a high dosage over seven years, appeared to prevent cognitive impairment in persons with a mean of 75 years of age. Potocnik found a modest zinc dose of 30 mg/day to postpone AD disease progression by 7 to 9 months.

References:
Tully CL, Snowdon DA, Markesbery WR. Serum zinc, senile plaques, and neurofibrillary tangles: findings from the Nun Study. Neuroreport. 1995 Nov 13;6(16):2105-8. Abstract

Yaffe K, Clemons TE, McBee WL, Lindblad AS; Age-Related Eye Disease Study Research Group. Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology. 2004 Nov 9;63(9):1705-7. Abstract

Potocnik FC, van Rensburg SJ, Park C, Taljaard JJ, Emsley RA. Zinc and platelet membrane microviscosity in Alzheimer's disease. The in vivo effect of zinc on platelet membranes and cognition. S Afr Med J. 1997 Sep;87(9):1116-9. Abstract

View all comments by Erik Jansson