Mechanisms of FH Protection Against Neovascular AMD

Abstract

A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NT al region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CT al region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential.

FH-like protein 1-Y402H mutation promoted microglial synapse phagocytosis and cognitive impairment in Alzheimer's disease model

“…The experiments demonstrated that Y402H mutation decreased a nity for HS [33] and the weaker binding of CFH Y402H to HS could reduce the activity of CFH for complement regulation including C3 [33]. Though CFH has other functions to protect disease beyond the association with C3 [34], our data indicated that FHL-1 Y402H had strongly associated with C3-mediated synapse phagocytosis by microglia in AD pathogenesis. Microglia not only engulf synapses but also amyloid [35,36].…”

Crosstalk Between Microglia and Müller Glia in the Age-Related Macular Degeneration: Role and Therapeutic Value of Neuroinflammation

“…In a mouse model nAMD, intravitreal injection of recombinant FH (recFH) reduced CNV area as effectively as anti-VEGF antibodies. recFH also reduces the deposition of microglia recruitment markers in C3 cut fragments, MAC, and CNV lesions [ 148 ]. These findings suggest that modulating the complement cascade activation provides potential reference value for the clinical treatment of AMD.…”

Factor H’s Control of Complement Activation Emerges as a Significant and Promising Therapeutic Target for Alzheimer’s Disease Treatment

“…This form of FH contains all expected human glycosylations. Moreover, we have previously shown that the injection of human plFH is active in regulating endogenous complement activation in mice by reducing the cleavage of C3 into C3b [25]. A quantity of 50 µg of plFH was chosen based on our previous results obtained for the treatment of laser-induced age-related macular degeneration in mice [25].…”

“…FH prevents the formation and accelerates the decay of the C3/C5 convertases and assists in the degradation of C3b, thereby breaking the complement-positive C3 convertase complex feedback loop (Supplemental Figure S1a). FH may also regulate complement-independent processes such as apoptosis, angiogenesis or oxidative stress, which are involved in the development of AD [24,25]. In the brain of AD patients, the levels of C3, the major compound of complement activation, are upregulated [26].…”