Considering Anti-Amyloid Immunotherapy

Amyloids are solid masses that form in tissues as a result of misfolded proteins. The amount of amyloid increases with age, perhaps due to a failure of mechanisms that keep the levels of damaged or misfolded proteins under control, and this is thought to cause harm and contribute to degenerative aging. In most cases researchers are still lacking a full understanding of the mechanisms involved, however. At the very least having solid clumps and fibrils present where they shouldn't exist can disrupt tissue integrity or even cause larger scale issues such as clogging blood vessels.

One approach to removing amyloid involves the use of the immune system. Immune therapies direct immune cells to attack and break down a specific target, and much of the innovation in their use as a therapy to remove amyloid is happening in the Alzheimer's research community. That condition is associated with amyloid beta, but we can hope that any successful therapies will prove adaptable to other forms of amyloid and thus applicable to human rejuvenation.

Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. AD is strongly associated with Amyloid-beta (Abeta) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics.

Within the past decade convincing data has arisen positioning the soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD. However, different Abeta aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Abeta is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function.

Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Abeta-aggregates than to focus on a single aggregate species for immunization.

Link: http://www.immunityageing.com/content/10/1/18/abstract

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