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

Abstract

Accumulation of amyloid-β (Aβ) peptides in the brain is one of the central pathogenic events in Alzheimer's disease (AD). However, why and how Aβ aggregates within the brain of AD patients remains elusive. Previously, we demonstrated hemoglobin (Hb) binds to Aβ 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 Aβ in vitro and in vivo and report the following observations: 1) the binding of Hb to Aβ required iron-containing heme; 2) other heme-containing proteins, such as myoglobin and cytochrome C, also bound to Aβ; 3) hemin-induced cytotoxicity was reduced in neuroblastoma cells by low levels of Aβ; 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 Aβ 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, Aβ 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.

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

“…Furthermore, nitric oxide and its metabolites have high affinity for HBB, and HBB can be considered a protectant from oxidative and nitrosative stress [65]. Besides nitric oxide scavenging, HBB is capable of binding Aβ and enhancing its aggregation ability due to the presence of the iron core; HBB was previously shown to localize to amyloid plaques in AD brains [66]. It is thus possible that in NDAN HBB is promoting Aβ removal from the synapses which is supportive of our previous findings [24].…”

Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

“…Recent evidence shows that Aβ can induce intracellular heme synthesis and iron uptake in vitro [9,32] . Heme can bind to Aβ to form heme-Aβ, promoting [24,26,33,34] .…”

Apolipoprotein E and Sex Bias in Cerebrovascular Aging of Men and Mice

“…A direct role for microvascular leakage in plaque formation was suggested by the rapid induction of Aβ42 deposits in FAD mice by a needle stab into the hippocampus that caused a fine trace of blood; injections of hemoglobin stimulated larger amounts of Aβ around the needle track [63]. In vitro, low levels of iron (<1 μmole) promote the aggregation of Aβ peptides, a catalytic effect blocked by chelation [64].…”