Moderator of 3 Sessions
Presenter of 4 Presentations
A MAGICAL CASE: A STORY OF THE CELL-SPECIFIC EFFECTS OF C3-MEDIATED NEURODEGENERATION
Abstract
Aims
Synapse loss is a critical feature of Alzheimer’s disease (AD). C3 is the molecule at which multiple complement signaling pathways converge and has emerged as a key factor in synapse elimination during aging and AD. Here, we aimed to define the underlying cell-specific mechanisms of either microglia or astrocytes that lead to C3-dependent synaptic toxicity and neurodegeneration.
Methods
We generated cell-specific C3 tamoxifen (TAM)-inducible conditional knock-out (KO) mice to allow for specific C3 depletion in microglia (C3mg-iKO) and astrocytes (C3as-iKO). Young adult female and male mice were injected intraperitoneally with either corn oil (CO; control) or TAM once every 24h for 5 consecutive days (75mg/kg body weight). Following treatment mice were aged and underwent a battery of behavioral, biochemical, and histological analyses.
Results
Aged TAM-treated C3mg-iKO mice performed significantly better in behavioral tests of spatial memory, showed a modest lowering of C3 and C1q protein levels in the hippocampus and a 30% lowering of C3 mRNA expression levels compared to controls. Aged TAM-treated C3as-iKO mice demonstrated a modest increase in post-synaptic density in the hippocampus and a 50% lowering of C3 and clusterin mRNA astrocyte expression levels compared to controls. Furthermore, C3 lowering in astrocytes significantly protected hippocampal synapses from Aβ-dimer-mediated LTP impairment in TAM-treated C3as-iKO mice. As expected, neither model resulted in significant changes in serum C3 protein levels.
Conclusions
Our results implicate glial cells in C3-mediated neurodegeneration and highlight the importance of further understanding the interactions between C3 and the glial cells that lead to synapse loss during aging and AD. Further investigation of these interactions may play a key role in developing therapeutic targets for tackling AD and other neurodegenerative disorders.
JUNIOR FACULTY AWARD PRESENTATIONS
POTENTIAL MECHANISMS AND MITIGATION STRATEGIES FOR ANTI-AMYLOID ANTIBODY-INDUCED ARIA
Abstract
Abstract Body
Background: Recent FDA approvals of two anti-amyloid antibodies, aducanumab and lecanemab, and positive Phase 3 results for a third anti-amyloid antibody, donanemab, for the treatment of early-stage Alzheimer’s disease (AD) provide the first disease-modifying-treatments. However, vascular side effects known as Amyloid Related Imaging Abnormalities due to edema (ARIA-E) or microhemorrhages (ARIA-H) were observed, especially in ApoE4 carriers, and were mostly asymptomatic and transient, but in rare cases caused hemorrhages. Understanding and mitigating ARIA is an urgent unmet need. Cerebral amyloid angiopathy (CAA) may be a key factor: ApoE4 carriers are predisposed to CAA, have impaired Aβ clearance across the BBB, and are at higher risk for ARIA.
Methods: First, 17.5-mo-old APP/PS1;hApoE4 mice were chronically immunized by i.p. injection weekly with 500 µg 3D6-L, a murine version of bapineuzumab, or anti-mouse IgG2a for 13 weeks. Second, in a pilot study, 17-mo-old APPNL-F/NL-F;hApoE4 mice were acutely immunized (i.p.) with 750 µg 3D6-L weekly for 1, 2 or 3 weeks or anti-murine IgG2a for 2 weeks and euthanized 24 h later. Immunofluorescent staining for IgG2a, amyloid, complement, immune cells and BBB leakage are ongoing. Blood biomarkers will be evaluated.
Results: Chronic dosing with 3D6-L induced meningeal microhemorrhages. Both acute and chronic 3D6-L treatment led to increased antibody colocalization with CAA, associated with elevated C1q and iC3b staining. MMP9 and von Willebrand Factor were also observed in the same vessels in the chronic study (the acute study is ongoing).
Conclusions: We hypothesize that anti-amyloid antibodies bind vascular amyloid and trigger a local immune response, including complement activation. The rationale and supporting evidence for co-treatment with anti-inflammatories such as a GLP-1R agonist, an anti-C1s antibody, or an anti-APOE antibody (HAE-4) will be presented.