Targeting the amyloid precursor protein interactome in Wnt signalling provides novel therapeutic strategies for Alzheimer’s disease
DOI:
https://doi.org/10.60988/p.v37i2S.130Keywords:
Alzheimer’s disease; drug discovery; Wnt signalling; drug repositioning; transcriptomicsAbstract
Alzheimer’s disease (AD) is characterised by progressive synaptic dysfunction, cognitive decline, and pathological hallmarks including amyloid-beta (Aβ) accumulation and tau hyperphosphorylation. Aβ disrupts Wnt signalling by inducing Dickkopf-1 (Dkk1); a secreted antagonist that promotes a pathological shift from canonical Wnt/β-catenin to non-canonical planar cell polarity signalling. Crucially, the amyloid precursor protein (APP) interacts with key components of the Wnt pathway, including the co-receptor LRP6 (low-density lipoprotein receptor-related protein 6). This places APP at the centre of a regulatory network – the APP interactome – that modulates synapse stability, Aβ production, and transcriptional homeostasis. In our recent studies, we explored how therapeutic modulation of this network restores synaptic health and cognitive function in AD models. We show that the ROCK (Rho-associated coiled-coil kinase) inhibitor fasudil reverses AD-associated transcriptional signatures in vivo and blocks Aβ-induced synaptotoxicity. Furthermore, we report a novel Dkk1-LRP6 disruptor peptide that restores canonical Wnt signalling, reduces Aβ generation, and prevents cognitive deficits in vivo. These data position the APP-Wnt interactome as a rich source of therapeutic targets, and establish new strategies for the restoration of synaptic resilience in AD.
References
DeKosky S.T., Scheff S.W. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann. Neurol. 27(5), 457–464, 1990. DOI: 10.1002/ana.410270502
Zheng H., Koo E.H. Biology and pathophysiology of the amyloid precursor protein. Mol. Neurodegener. 6(1), 27, 2011. DOI: 10.1186/1750-1326-6-27
Elliott C., Rojo A.I., Ribe E., Broadstock M., Xia W., Morin P., et al. A role for APP in Wnt signalling links synapse loss with β-amyloid production. Transl. Psychiatry 8(1), 179, 2018. DOI: 10.1038/s41398-018-0231-6
Killick R., Ribe E.M., Al-Shawi R., Malik B., Hooper C., Fernandes C., et al. Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Mol. Psychiatry 19(1), 88–98, 2014. DOI: 10.1038/mp.2012.163
Sellers K.J., Elliott C., Jackson J., Ghosh A., Ribe E., Rojo A.I., et al. Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. Alzheimers Dement. 14(3), 306–317, 2018. DOI: 10.1016/j.jalz.2017.09.008
Elliott C., Jackson J., Findlay J., Williams G., Ghosh A., Ribe E., et al. Blocking the Dkk1-LRP6 interaction prevents acute amyloid-β-driven cognitive impairment. Cell. Signal. 131, 111716, 2025. DOI: 10.1016/j.cellsig.2025.111716
Killick R., Elliott C., Ribe E., Broadstock M., Ballard C., Aarsland D., et al. Neurodegenerative disease associated pathways in the brains of triple transgenic Alzheimer’s model mice are reversed following two weeks of peripheral administration of fasudil. Int. J. Mol. Sci. 24(13), 11219, 2023. DOI: 10.3390/ijms241311219
Bourhis E., Wang W., Tam C., Hwang J., Zhang Y., Spittler D., et al. Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6. Structure 19(10), 1433–1442, 2011. DOI: 10.1016/j.str.2011.07.005
