Alzheimer Disease (AD)

Alzheimer disease (AD) is a relentlessly progressive neurodegenerative disease. It is the most common form of dementia. The disease slowly destroys brain function, affecting memory and reasoning, and eventually robbing the individual of any ability to carry out everyday activities.

AD represents an emerging crisis as there are presently no approved disease modifying agents. Currently there are an estimated 35 million cases worldwide. The numbers are expected to exceed 100 million by 2050 if no effective interventions are found. In the decade 2002-2012, 244 compounds were assessed in AD clinical trials. Of these, 243 failed (Cummings et al., 2014). While there are a handful of drugs approved for treating symptoms, there are none that are considered to be disease-modifying.

It has long been known that beta amyloid protein deposits in brain are a hallmark of the disease. These beta amyloid plaques are believed to be the primary cause of the disease and are naturally targeted by the opsonizing components of complement. Specifically, the complement system is initiated by C1q binding to beta amyloid protein (Rogers et al., 1992). It has also been demonstrated that the membrane attack complex ‘decorates’ damaged neurites in the vicinity of the Abeta deposits, indicating self-damage by the complement system (McGeer et al., 1989). Taken together, these data illustrate that the opsonizing aspects of the classic initiation pathway of complement needs to be preserved so that phagocytosis of the beta amyloid deposits can occur, while the membrane attack complex needs to be selectively blocked so that self-damage to host neurons can be eliminated.

What is clearly needed is an orally effective agent that will interrupt the accumulation of beta amyloid and the pro-inflammatory consequences of that accumulation. Beta amyloid is a powerful activator of the complement system and over activity is known to kill host cells in a process known as bystander lysis. The McGeer laboratory demonstrated that this process is occurring in AD more than two decades ago and that people on long-term non-steroidal anti-inflammatory drugs (NSAIDs) for unrelated conditions had a statistically significant sparing of AD. Since then, more than 12 epidemiological studies and fourteen transgenic mouse studies have confirmed these findings.

AUR1107 is a promising agent for the treatment of AD because it is a powerful inhibitor of the terminal complement cascade. AUR1107 was found to preserve behavioral function in a preliminary evaluation in a transgenic mouse model of AD. No toxicity or side effects were observed in the AUR1107-fed mice and no pathology was detected in post-mortem tissues of these mice (Lee et al. 2012).

 

References & Further Reading

  • Cummings JL, Morstorf T, Zhong K, 2014. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimer’s Research and Therapy, 6:37. http://alzres.com/content/6/4/37.
  • Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD, LaFerla FM et al (2009) Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J Immunol 183(2):1375–1383.
  • Hamilton G, Evans KL, Macintyre DJ, Deary IJ, Dominiczak A, Smith BH et al (2012) Alzheimer’s disease risk factor complement receptor 1 is associated with depression. Neurosci Lett 510(1):6–9.
  • Lee M, Guo JP, Schwab C, McGeer EG, McGeer PL. Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex. Neurobiol Aging. 2012;33:2237- 2246. doi:10.1016/jneurobiolaging.2011.12.005
  • Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10):1094–1099
  • McGeer PL, Akiyama H, Itagaki S, McGeer EG. Immune system response in alzheimer’s disease. Can J Neurol Sci. 1989;16:516-527 McGeer PL, Akiyama H, Itagaki S, McGeer EG. 1989. Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neuroscience Letters 107: 341-346
  • Proitsi P, Lupton MK, Dudbridge F, Tsolaki M, Hamilton G, Daniilidou M et al (2012) Alzheimer’s disease and age- related macular degeneration have different genetic models for complement gene variation. Neurobiol Aging 33(8):1843.e9-1843.e17.
  • Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, Civin WH, Brachova L, Bradt B, Ward P, Lieberburg I. Complement activation by b-amyloid in Alzheimer disease. 1992. Proc Natl Acad Sci USA 89:10016-10020, 1992.
  • Veerhuis R, Nielsen HM, Tenner AJ (2011) Complement in the brain. Mol Immunol 48(14):1592–1603.