Rethinking amyloid (not beta amyloid)

Dementia News 80, February 2008

This month’s Editorial is devoted to a rather unusual topic, only marginally linked to Alzheimer’s disease (AD), that is: amyloid as a depot for the formulation of long acting drugs. However the speculation that the paper by Maji et al. raises, may well have long term fall outs on the understanding of beta amyloid dynamics and functions in the brain.

The point taken by the Authors is straightforward: amyloids are highly organized protein aggregates that self-polymerize by recruiting their soluble protein counterpart and remain stable against harsh physical, chemical, and biochemical conditions. These properties make amyloids attractive for applications in various fields, including nanotechnology, bioengineering, and in the formulation of long-acting drugs, which are active over extended periods of time (days or weeks). This concept has been tested by the Authors with a family of short- and long-acting analogs of gonadotropin-releasing hormone (GnRH), indeed showing that amyloids can act as a source for the sustained release of biologically active peptides. It should be noted that amyloid is a general term referred to the peculiar beta sheet pleated conformation that a protein may assume; beta amyloid in AD is just one of the many possible known amyloids. There are several amyloids producing degenerative illnesses as well as others that have beneficial biological activities, as reviewed in the quoted paper. Since proteins with nonhomologous sequences form amyloid fibrils, under certain conditions, many proteins and peptides can form amyloid-like fibrils.

In particular the Authors have show that GnRH analogs are able to form amyloids in vivo and that the formation of fibrils of a peptide drug can prolong its duration of action. In order to do so the Authors had to do a series of control experiments which may have relevance for beta amyloid studies. For example they had to show that the amyloids of GnRH analogs are not toxic, i.e. the toxicity of amyloid peptides may depend upon the specific peptide involved, not just residing in the fibrillar structure. The Authors also showed that the injected amyloids of GnRH analogs do not act as the seeds of the host GnRH nor do cross seed with other amyloid proteins of putative pathological relevance such as, for example, alpha-synuclein.

Using the Authors’ words: “It follows that in striking contrast to the original association of amyloids with diseases, amyloids might also be useful in the treatment of diseases”.


prof. Stefano Govoni
Department of Experimental and Applied Pharmacology, University of Pavia, Italy

Send a comment

Past issues

Home