Alzheimer’s disease: Destroying the memories of our Elders

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive dysfunction and progressive memory loss. Нe complex disease pathology includes three prominent pathological hallmarks: extracellular plaques composed of Aβ peptide aggregates, intracellular neurofibrillary tangles of tau protein, and chronic neuroinflammation. Нe most commonly accepted mechanism underlying AD pathology until recently has been the amyloid hypothesis. It postulates that overproduction of Aβ peptides and their subsequent pathological aggregates play a central role in AD pathogenesis. Hence for decades, the development of therapeutic approaches was focused on modifying the Aβ levels by preventing its aggregation, hindering its production, and/or enhancing its degrading activity. Several therapeutic approaches that targeted Aβ aggregation were tested in clinical trials, however by now, none of them showed consistent improvements in AD patients. Recently monoclonal antibodies (mAb) against Aβ have advanced into late clinical trials as reviewed in Liu et al., but the most advanced mAbs Bapineuzumab and Solanezumab failed to meet their clinical endpoints in phase III clinical studies. However, efforts still go on and only recently a newly developed mAb showed very promising results. Aducanumab that selectively targets aggregated Aβ was found to reduce cerebral Aβ in a dose- and time-dependent manner accompanied by a slowing of clinical decline in a phase Ib clinical trial. Further large scale studies are necessary to demonstrate if Aducanumab is able to halt or reverse cognitive decline in AD patients. In contrast to the passive immunotherapy approaches the development of active immunization targeting Aβ is limited. Only few vaccines have advanced to phase II clinical development. Using our proprietary AFFITOME-technology we developed the anti-Aβ peptide vaccine AD02. The administration of AD02 to transgenic mouse model of AD was able to reduce the cerebral amyloid burden, and the associated neuropathological alterations, and improved the cognitive functions. Since AD is considered to be a multifactorial disease, not only Aβ aggregation, but many over-lapping processes contribute to neuronal degeneration and cognitive loss, and especially the role of neuroinflammation was strengthened in the pathogenesis and exacerbation in AD in the last years. Aβ aggregates cause direct cytotoxicity and self-propagation, but also a constant, selfsustaining inflammatory environment by prolonged activation of astroglial and microglial cells.

Journal of Aging Science is planning to release issue on Alzheimers where you can provide any updated information related within the field. We will be publishing it as first priority among all articles.

Regards
John George
Journal of Aging Science