Development of new drugs for the treatment of Alzheimer's Disease

Evaluation of Acitretin as α-secretase activator and modulator of the immune system

Amyloid-plaques which are typical for Alzheimer's Disease develop due to wrong splicing of the amyloid-precursor-protein (APP). Under normal circumstances, α-secretase demerges neuroprotective APPSα-peptide which can be measured in cerebro-spinal fluid. Thus it would make sense to investigate substances that activate non-amyloidogenic metabolic pathways for future therapies of Alzheimer's Disease, i.e. the so called α-secretase activators.

Prof. Dr. Dr. hc. F. Fahrenholz, Fr. Dr. K. Endres and co-workers recently demonstrated in laboratory and animal experiments, that Acitretin, a substance related to vitamin A that is also used for the treatment of psoriasis, is a strong α-secretase activator.

In a randomized, double blind and placebo controlled study jointly conducted by the groups of Prof. Dr. Fellgiebel and PD Dr. Endres to demonstrate this expected mode of action of Acitretin by measuring the APPsα concentration in the cerebro-spinal fluid of treated patients of early and mild AD compared to placebo. The project was funded by the Alzheimer Research Initiative (AFI).

Citations

1. Endres K, Fahrenholz F, Lotz J, Hiemke C, Teipel S, Lieb K, Tüscher O, Fellgiebel A. Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin. Neurology 2014: doi: 10.1212/WNL.0000000000001017

2. Endres K, Fahrenholz F. Regulation of alpha-secretase ADAM10 expression and activity. Experimental brain research Experimentelle Hirnforschung Experimentation cerebrale 2012; 217(3-4): 343-52.

3. Corrigan F, Vink R, Blumbergs PC, Masters CL, Cappai R, van den Heuvel C. sAPPalpha rescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury. Journal of neurochemistry 2012; 122(1): 208-20.

4. Postina R, Schroeder A, Dewachter I, et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. The Journal of clinical investigation 2004; 113(10): 1456-64.

5. Endres K, Fahrenholz F. Upregulation of the alpha-secretase ADAM10--risk or reason for hope? The FEBS journal 2010; 277(7): 1585-96.

6. Tippmann F, Hundt J, Schneider A, Endres K, Fahrenholz F. Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2009; 23(6): 1643-54.

7. Kitaoka K, Shimizu N, Ono K, et al. The retinoic acid receptor agonist Am80 increases hippocampal ADAM10 in aged SAMP8 mice. Neuropharmacology 2013; 72C: 58-65.

8. Melino G, Draoui M, Bernardini S, Bellincampi L, Reichert U, Cohen P. Regulation by retinoic acid of insulin-degrading enzyme and of a related endoprotease in human neuroblastoma cell lines. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 1996; 7(6): 787-96.

9. Cramer PE, Cirrito JR, Wesson DW, et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 2012; 335(6075): 1503-6.

10. Chakrabarty P, Jansen-West K, Beccard A, et al. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2010; 24(2): 548-59.

11. Takasaki J, Ono K, Yoshiike Y, et al. Vitamin A has anti-oligomerization effects on amyloid-beta in vitro. Journal of Alzheimer's disease : JAD 2011; 27(2): 271-80.