Developments in the Role of Iron Imbalance in the Pathogenesis of Alzheimer's Disease

Abstract

Iron load is closely associated with the initiation and progression of Alzheimer's disease (AD) . Although age-dependent deposition of β-amyloid (A β) in senile plaques (SPs) , and neurofibrillary tangles (NFTs) formed by accumulation of hyperphosphorylated tau proteins are two major pathological features of AD, there are still many different views on the inducing factors of SPs and NFTs. We reviewed the new developments in the relationship between imbalance of brain iron homeostasis and the pathogenesis of AD, with a summary presented as follows: (1) Age-related iron deposits in different brain regions may damage normal cognitive function and behavior. (2) Iron imbalance and oxidative stress may together or independently promote Aβ overproduction by activating β- or γ-secretases and inhibiting α-secretase, and also cause tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β, cyclin-dependent protein kinase-5, and inhibiting protein phosphatase 2A. Iron imbalance-induced changes will in turn aggravate brain iron deposition and distribution. The vicious circle between iron imbalance and Aβ/tau anomalies may eventually lead to AD. (3) Iron overload may also directly or indirectly injure organelles, causing endoplasmic reticulum stress, mitochondrial and autophagy dysfunction, and damaging synaptic function via inducing or aggravating the aggregation or accumulation of A βand tau. At the same time, hydroxyl radicals produced via the Fenton reaction associated with abnormal iron metabolism, may trigger oxidative stress, destroy the structure and function of cell lipids, protein and DNA, eventually leading to cell death. (4) Given the limitations and side effects of long-term application of traditional iron chelators, alpha-lipoic acid and lactoferrin as self-synthesized naturally small molecules, are expected to be applied to clinical practice, for they have shown very intriguing biological activities in blocking Aβ-aggregation, tau hyperphosphorylation and neuronal damage. We believe that iron-targeted therapies are a promising direction for the treatment of AD.

Keywords

• |alzheimer disease|iron imbalance|amyloid beta-peptides|tau hyperphosphorylation|chelating agents|pathogenesis