Interactions between Amyloid-β and Hemoglobin: Implications for Amyloid Plaque Formation in Alzheimer's Disease

Accumulation of amyloid-beta (A beta) peptides in the brain is one of the central pathogenic events in Alzheimer's disease (AD). However, why and how A beta aggregates within the brain of AD patients remains elusive. Previously, we demonstrated hemoglobin (Hb) binds to A beta and co-localizes with the plaque and vascular amyloid deposits in post-mortem AD brains. In this study, we further characterize the interactions between Hb and A beta in vitro and in vivo and report the following observations: 1) the binding of Hb to A beta required iron-containing heme; 2) other heme-containing proteins, such as myoglobin and cytochrome C, also bound to A beta; 3) hemin-induced cytotoxicity was reduced in neuroblastoma cells by low levels of A beta; 4) Hb was detected in neurons and glial cells of post-mortem AD brains and was up-regulated in aging and APP/PS1 transgenic mice; 5) microinjection of human Hb into the dorsal hippocampi of the APP/PS1 transgenic mice induced the formation of an envelope-like structure composed of A beta surrounding the Hb droplets. Our results reveal an enhanced endogenous expression of Hb in aging brain cells, probably serving as a compensatory mechanism against hypoxia. In addition, A beta binds to Hb and other hemoproteins via the iron-containing heme moiety, thereby reducing Hb/heme/iron-induced cytotoxicity. As some of the brain Hb could be derived from the peripheral circulation due to a compromised blood-brain barrier frequently observed in aged and AD brains, our work also suggests the genesis of some plaques may be a consequence of sustained amyloid accretion at sites of vascular injury.