| First Author | Zelek WM | Year | 2024 |
| Journal | Brain Behav Immun | Volume | 118 |
| Pages | 355-363 | PubMed ID | 38485063 |
| Mgi Jnum | J:346660 | Mgi Id | MGI:7615873 |
| Doi | 10.1016/j.bbi.2024.03.017 | Citation | Zelek WM, et al. (2024) Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia. Brain Behav Immun 118:355-363 |
| abstractText | Complement is dysregulated in the brain in Alzheimer's Disease and in mouse models of Alzheimer's disease. Each of the complement derived effectors, opsonins, anaphylatoxins and membrane attack complex (MAC), have been implicated as drivers of disease but their relative contributions remain unclarified. Here we have focussed on the MAC, a lytic and pro-inflammatory effector, in the App(NL-G-F) mouse amyloidopathy model. To test the role of MAC, we back-crossed to generate App(NL-G-F) mice deficient in C7, an essential MAC component. C7 deficiency ablated MAC formation, reduced synapse loss and amyloid load and improved cognition compared to complement-sufficient App(NL-G-F) mice at 8-10 months age. Adding back C7 caused increased MAC formation in brain and an acute loss of synapses in C7-deficient App(NL-G-F) mice. To explore whether C7 was a viable therapeutic target, a C7-blocking monoclonal antibody was administered systemically for one month in App(NL-G-F) mice aged 8-9 months. Treatment reduced brain MAC and amyloid deposition, increased synapse density and improved cognitive performance compared to isotype control-treated App(NL-G-F) mice. The findings implicate MAC as a driver of pathology and highlight the potential for complement inhibition at the level of MAC as a therapy in Alzheimer's disease. |
