Abstract
Alzheimers Dement. 2025 Dec;21 Suppl 7:e108571. doi: 10.1002/alz70861_108571.
ABSTRACT
BACKGROUND: Fraktaline, otherwise known as CX3CL1, is a chemokine that can act on microglia to promote the release of matrix metalloproteinases (MMPs). Additionally, CX3CL1 can upregulate MMP-9 which has been associated with alterations in memory and vasculature remodeling. MMP-9 has also been shown to interact with tau protein, as well as APP processing, and its levels are higher in APOE4 carriers. Therefore, we examined the role of MMP-9 in the CX3CL1-CX3CR1 pathway in APOE4 carriers (APOE+) compared to noncarriers (APOE-), as well as its implication on tau and amyloid pathology.
METHODS: Cerebrospinal fluid samples were collected from 116 cognitively unimpaired veterans, aged 50-76, participating in the Brain Amyloid and Vascular Effects of Eicosapentaenoic acid (BRAVE) study (NCT02719327). We designed a custom electrochemiluminescent assay to quantify MMP-9 levels using the Meso Scale Discovery SQ120. A NULISAseq CNS Disease Panel was used to quantify CX3CL1, ptau217, Aβ40, Aβ42 and the Roche Cobas Analyzer measured total tau.
RESULTS: In APOE- individuals, CX3CL1 had a direct effect on ptau217 levels (B = 0.77, SE = 0.17, p < .001, 95% CI [0.42, 1.11], with a standardized effect of β=0.44) with no mediating role of MMP-9 (β = -0.0006, BootSE = 0.01, 95% CI [-0.025, 0.021]). CX3CL1 positively correlated with ptau217 (p <.001), Aβ40 (p <.001) and Aβ42 (p <.001). We found a negative correlation between CX3CL1 and ptau217/total tau (p <.001), as well as ptau217/Aβ42 (p =.013). MMP-9 did not correlate with Aβ40, Aβ42, Aβ42/Aβ40, ptau217, ptau217/total tau, or ptau217/Aβ42 (p >0.05). However, in APOE+ carriers, MMP-9 played a significant mediating role in the pathway involving CX3CL1 on ptau217 (β = 0.46, 95% CI [0.10, 0.75]). Importantly, MMP-9 had a positive correlation between ptau217 (p <.001), CX3CL1 (p <.001), Aβ40 (p <.001) and a negative relationship with Aβ42/Aβ40 (p =.013) and ptau217/total tau (p <.001).
CONCLUSION: We propose that APOE+ carriers experience a dysregulated CX3CL1 signaling pathway that is mediated by MMP-9 with implications on tau regulation. Specifically, MMP-9 is recruited into the CX3CL1 signaling pathway to reduce ptau217 phosphorylation in APOE+ carriers. If replicated, targeting MMP-9 could be beneficial in therapeutic interventions focusing on the reduction of ptau217 pathology in neurodegenerative disorders in those who are APOE+.
PMID:41434527 | DOI:10.1002/alz70861_108571
UK DRI Authors
