Alzheimer's disease (AD), the most common form of dementia, presents an immense challenge to both patients and the healthcare system. With limited treatment options available, especially for late-stage AD, novel therapeutic strategies are urgently needed. Our recent study, published in Nature Portfolio, addresses this gap by investigating the potential of a molecular chaperone, BRICHOS, to target late-stage AD-like pathology in a mouse model. Our findings (Fig. 1) suggest that BRICHOS not only reduces amyloid plaque load but also mitigates neuroinflammation and, remarkably, restores the expression profiles of genes previously shown¹ to be relevant for the pathology in mouse models as well as in AD patients.

Current therapeutic approaches, such as monoclonal antibodies targeting amyloid-β (Aβ) plaques, have shown efficacy in early symptomatic AD². However, AD is often diagnosed at a later stage, when cognitive decline is already significant. Our paper focuses on finding effective treatments that can modify the disease's course even when pathology is well established. BRICHOS is a molecular chaperone that inhibits amyloid fibril formation by interacting with the surface of fibrils, thereby preventing the formation of neurotoxic amyloid species³. In previous studies, BRICHOS has demonstrated the ability to reduce Aβ-induced toxicity in vitro and in animal models⁴, but its effects on advanced AD pathology were not known. We used a recombinant form of the BRICHOS chaperone, engineered for stability⁵, to investigate its potential benefits in APP^NL-G-F knock-in mice that progressively develop AD-like pathology from the age of two months⁶.

We treated 9-month-old APP^NL-G-F knock-in mice with intravenous injections of recombinant human BRICHOS twice a week for three months. We monitored the animals' health, amyloid plaque load, astro- and microgliosis, and gene expression in microglia—the brain's resident immune cells. The results (Fig. 1) showed that BRICHOS treatment significantly reduced the amyloid plaque burden in the hippocampus and cortex, and decreased the activation of astrocytes and microglia, key players in neuroinflammation associated with AD.

One of the most intriguing findings was the normalization of gene expression in microglia following BRICHOS treatment (Fig. 1). Several genes linked to AD pathology, such as clusterin and glial fibrillary acidic protein (GFAP), showed expression levels that returned to those observed in healthy controls. This suggests that BRICHOS may not only reduce plaque load and toxicity, but also modulate the neuroinflammatory response in late-stage AD.

Figure 1. Summary of treatment effects of BRICHOS on late-stage AD-like pathology in App^NL-G-F knock-in mice. Veh, vehicle (PBS); wt, wildtype mice; BBB, blood-brain barrier.

Our results support the potential of BRICHOS as a therapeutic candidate for AD, especially in advanced stages where current treatments fall short, and further work is warranted to translate these findings into clinical applications. Finallly, our study supports that targeting amyloid-induced toxicity can alter the disease course, which is potentially relevant also for other amyloid associated diseases like Parkinson´s disease and type 2 diabetes.

References

1          Chen, W. T. et al. Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease. Cell 182, 976-991 e919 (2020). https://doi.org:10.1016/j.cell.2020.06.038

2          Wicker, A., Shriram, J., Decourt, B. & Sabbagh, M. N. Passive Anti-amyloid Beta Monoclonal Antibodies: Lessons Learned over Past 20 Years. Neurol Ther (2024). https://doi.org:10.1007/s40120-024-00664-z

3          Leppert, A. et al. A new kid in the folding funnel: Molecular chaperone activities of the BRICHOS domain. Protein Sci. 32, e4645 (2023). https://doi.org:ARTN e4645

10.1002/pro.4645

4          Manchanda, S. et al. Intravenous treatment with a molecular chaperone designed against β-amyloid toxicity improves Alzheimer’s disease pathology in mouse models. Mol. Ther. 31, 487-502 (2023). https://doi.org:10.1016/j.ymthe.2022.08.010

5          Chen, G. et al. Augmentation of Bri2 molecular chaperone activity against amyloid-beta reduces neurotoxicity in mouse hippocampus in vitro. Commun Biol 3, 32 (2020). https://doi.org:10.1038/s42003-020-0757-z

6          Saito, T. et al. Single App knock-in mouse models of Alzheimer's disease. Nat. Neurosci. 17, 661-663 (2014). https://doi.org:10.1038/nn.3697