Amyloid-Targeted Metal Chelation, Anti-Oxidative Stress, and Anti- Inflammation as Potential Alzheimers Therapies

A.      Fydrych; R.   D.   Moir; C.      Huang; Y.      Shi; J.   T.   Rogers; X.      Huang

doi:10.2174/157340708786305989

Abstract

Alzheimers disease (AD), which accounts for over 80 percent of senile dementia cases, is a polygenic and multifactorial complex disease. However, an overwhelming body of data suggests that the key to AD pathology lies in the biology of a small protein called the Aβ peptide that forms the proteinaceous deposits known as Aβ amyloid that characterizes AD. Considerable progress has been made in understanding the metabolic pathways that generate and clear Aβ. Less well understood are the neurochemical factors that may be important in promoting age-dependent Aβ amyloidosis, the likely precursor to AD. Findings suggest that cerebral biometal dyshomeostasis, oxidative stress, and microglia immune inflammatory responses are intimately involved in Aβ amyloid deposition and AD pathogenesis. With these new findings has come an increasing awareness of the potential of antioxidant/metal chelation/anti-inflammatory therapies as AD treatments. The major impediment to the use of metal chelators and antioxidants are their unfavorable drug profiles that include poor target specificity and low therapeutic potency. However, future development of new bifunctional and multifunctional molecules that contain both amyloid-binding and metal-chelating/antioxidant moieties, is thought to overcome many of the limitations of previous chelating and antioxidant drugs. Herein we have reviewed the pathogenic roles of brain biometal dysregulation, oxidative stress, and neuroinflammation in AD. We have also discussed the potentials of amyloid-targeted metal chelation, anti-oxidative stress, and anti-inflammation as potential Alzheimers therapies.

Keywords: Metals, oxidative stress, Alzheimer's disease, amyloid precursor protein, Aβ amyloidosis, metal chelator, antioxidant, neuroinflammation