Enhanced aggregation and β structure of amyloid β peptide after coincubation with C1Q

Abstract

Several lines of evidence now suggest that aggregation of soluble amyloid beta peptide (A beta) into a cross beta sheet configuration may be an important factor in mediating potential neurotoxicity of A beta. Synthetic A beta has been shown to self aggregate in vitro. Here, we demonstrate that coincubation of freshly solubilized A beta with C1q, a complement component known to bind A beta in vitro and to colocalize with A beta in vivo, results in as much as a 7-fold enhancement of A beta aggregation, as well as a 2-4-fold enhancement of beta structure within aggregates. The addition of C1q to preformed A beta aggregates also results in significantly increased resistance to aggregate resolubilization.

Absence of C1q Leads to Less Neuropathology in Transgenic Mouse Models of Alzheimer's Disease

“…For example, in addition to the increases in inflammatory indicators, the amount of fibrillar A␤ area in APPQϪ/Ϫ mice was found to be comparable with that in the APP mice, indicating that C1q does not have a detectable influence on A␤ deposition or fibrillogenesis in this in vivo model. Although this is in contrast to in vitro studies showing that purified C1q enhanced the kinetics of A␤ fibril formation (Webster et al, 1994), the observations here are consistent with the known association of multiple proteins with plaques in vivo, at least some of which may modulate A␤ fibrillogenesis (Pepys et al, 2002). Nevertheless, the model is not a perfect mimic of the human disease, with one important difference being the lack of neuronal cell death.…”

“…A␤ plaques accumulate at comparable levels in APP and APPQ؊/؊ mice C1q has been shown to bind to fA␤, enhance amyloid fibrillogenesis (Webster et al, 1994(Webster et al, , 1995Boyett et al, 2003), and block fibrillar amyloid uptake by microglia (Brazil et al, 2000;Webster et al, 2000). These in vitro observations led to the hypothesis that C1q could influence A␤ deposition.…”

Differences between the Pathogenesis of Senile Plaques and Congophilic Angiopathy in Alzheimer Disease

“…Al though the Ap of diffuse senile plaques is in a relatively "soluble" form, it is not cleared from the brain parenchy ma, which indicates that it is retained in the neuropil via binding to other factors. Several of the Ap-associated fac tors, such as ApoE, a r ACT, Clq, clusterin, and HSPG, can bind to Ap (71)(72)(73)(74)(75). The Ap-associated components a r ACT, ApoE (76), C lq (73) and HSPG (77) may accelerate Ap fibril formation, as was observed under various exper imental conditions.…”

C1q-induced LRP1B and GPR6 Proteins Expressed Early in Alzheimer Disease Mouse Models, Are Essential for the C1q-mediated Protection against Amyloid-β Neurotoxicity

“…C1q Alters A␤ Association with Neurons through Enhanced A␤ Aggregation-In addition to directly interacting with neurons to stimulate a neuroprotective program as described above, C1q has been shown to bind A␤ and enhance A␤ aggregation (43). To assess whether C1q may also protect neurons by affecting the association of A␤ with neurons, primary mouse immature neurons were incubated with fA␤, and association of A␤ was assessed by evaluating the co-localization between fA␤ and MAP-2 (Fig.…”