In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimers disease drug Dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease. With CONCERT, the remaining Pfizer and Medivation Phase III trial for Dimebon (latrepirdine) in Alzheimers disease failed in 2012, effectively ending the development in this indication.In another experiment using a rat model of Alzheimers disease, it was demonstrated that systemic administration of hypothalamic proline-rich peptide (PRP)-1 offers neuroprotective effects and can prevent neurodegeneration in hippocampus amyloid-beta 25–35. This suggests that there could be therapeutic value to PRP-1. Other avenues of investigation
Protein degradation offers therapeutic options both in preventing the synthesis and degradation of irregular proteins. There is also interest in upregulating autophagy to help clear protein aggregates implicated in neurodegeneration. Both of these options involve very complex pathways that we are only beginning to understand.The goal of immunotherapy is to enhance aspects of the immune system. Both active and passive vaccinations have been proposed for Alzheimers disease and other conditions; however, more research must be done to prove safety and efficacy in humans.A current therapeutic target for the treatment of Alzheimers disease is the protease β-secretase, which is involved in the amyloidogenic processing pathway that leads to the pathological accumulation of proteins in the brain. When the gene that encodes for amyloid precursor protein (APP) is spliced by α-secretase rather than β-secretase, the toxic protein β amyloid is not produced.
In Huntingtons disease, it is huntingtin.Transglutaminase substrates:
Amyloid-beta, tau, alpha-synuclein and huntingtin have been proved to be substrates of transglutaminases in vitro or in vivo, that is, they can be bonded by trasglutaminases by covalent bonds to each other and potentially to any other transglutaminase substrate in the brain.Transglutaminase augmented expression:
It has been proved that in these neurodegenerative diseases (Alzheimers disease, Parkinsons disease, and Huntingtons disease) the expression of the transglutaminase enzyme is increased.Presence of isopeptide bonds in these structures:
The presence of isopeptide bonds (the result of the transglutaminase reaction) have been detected in the abnormal structures that are characteristic of these neurodegenerative diseases.Co-localization:
Co-localization of transglutaminase mediated isopeptide bonds with these abnormal structures has been detected in the autopsy of brains of patients with these diseases. Management
The process of neurodegeneration is not well understood, so the diseases that stem from it have, as yet, no cures. Animal models in research
In the search for effective treatments (as opposed to palliative care), investigators employ animal models of disease to test potential therapeutic agents. Model organisms provide an inexpensive and relatively quick means to perform two main functions: target identification and target validation. Together, these help show the value of any specific therapeutic strategies and drugs when attempting to ameliorate disease severity. An example is the drug Dimebon by Medivation, Inc. In 2009 this drug was in phase III clinical trials for use in Alzheimers disease, and also phase II clinical trials for use in Huntingtons disease.