Early monocyte modulation by the non-erythropoietic peptide ARA 290 decelerates AD-like pathology progression

Alzheimer's disease (AD) pathology is characterized by amyloid-beta (A beta) deposition and tau hyperphosphorylation, accompanied by a progressive cognitive decline. Monocytes have been recently shown to play a major role in modulating A beta pathology, and thereby have been pointed as potential therapeutic targets. However, the main challenge remains in identifying clinically relevant interventions that could modulate monocyte immune functions in absence of undesired off-target effects. Erythropoietin (EPO), a key regulator of erythrocyte production, has been shown to possess immunomodulatory potential and to provide beneficial effects in preclinical models of AD. However, the transition to use recombinant human EPO in clinical trials was hindered by unwanted erythropoietic effects that could lead to thrombosis. Here, we used a recently identified nonerythropoietic analogue of EPO, ARA 290, to evaluate its therapeutic potential in AD therapy. We first evaluated the effects of early systemic ARA 290 administration on AD-like pathology in an early-onset model, represented by young APP/PS1 mice. Our findings indicate that ARA 290 early treatment decelerated A beta pathology progression in APP/PS1 mice while improving cognitive functions. ARA 290 potently increased the levels of total monocytes by specifically stimulating the generation of Ly6CLow patrolling subset, which are implicated in clearing A beta from the cerebral vasculature, and subsequently reducing overall A beta burden in the brain. Moreover, ARA 290 increased the levels of monocyte progenitors in the bone marrow. Using chimeric APP/PS1 mice in which Ly6CLow patrolling subset are selectively depleted, ARA 290 was inefficient in attenuating A beta pathology and ameliorating cognitive functions in young animals. Interestingly, ARA 290 effects were compromised when delivered in a late-onset model, represented by aged APP1/PS1. In aged APP/PS1 mice in which AD-like pathology is at advanced stages, ARA 290 failed to reverse A beta pathology and to increase the levels of circulating monocytes. Our study suggests that ARA 290 early systemic treatment could prevent AD-like progression via modulation of monocyte functions by specifically increasing the ratio of patrolling monocytes.

Automated summary

Using the non-erythropoietic analogue ARA 290 early in the treatment of an early-onset model in mice showed promising results in slowing down Aβ pathology progression and improving cognitive functions. ARA 290 specifically increased the levels of patrolling monocytes which are involved in clearing Aβ, thus reducing the overall Aβ burden in the brain.