Armand Tadjali

Introduction. Small vessel disease (SVD) is a marked by endothelial dysfunction and blood-brain barrier (BBB) breakdown leading to pathology of dementia, such as white matter damage (demyelination) and amyloid deposits in the brain^1,2. However, the mechanisms contributing to these pathologic changes remain unclear. Regulatory molecules that have been investigated include hypoxia inducible factor-1³, nitric oxide⁴, and heat shock protein 90 (HSP90)^1,2,5. Of these factors, HSP90, which consists of an alpha and a beta form^1,2, appears to contribute to dementia pathology. Studies have been done on both forms of HSP90, which allude to a deleterious action of the alpha protein and a beneficial, reparative mechanism of the beta protein^1,2,5. Methods. In a rat model of human SVD, brain microvascular endothelial cells (BMECs) were isolated and cultured to perform assays for tight junction integrity and protein secretion². Oligodendrocyte precursor cells (OPCs) from deep white matter were also analyzed². Protein assays were performed to assess the link between HSP90b, peroxisome proliferator activated receptor gamma (PPARg), and brain amyloid deposits in APP/PS1 transgenic mice (Alzheimer’s disease model) with and without Jujuboside A (JuA) treatment¹. The effect of HSP90 on pyroptosis, a form of programmed cell death, was evaluated⁵. Results. Endothelial dysfunction linked to reduced levels of tight junction proteins and increased secretion of HSP90a was found in BMECs from SVD rats². Treatment of OPCs with HSPa decreased the maturation of OPCs into myelinating oligodendrocytes². HSP90a also correlated with increased ATP11B dysfunction, which led to a lower myelination of neighboring oligodendrocytes in areas near the BBB². HSP90b, on the other hand, was shown to have a beneficial effect on the outcome of mice with beta amyloid plaque deposits in SVD¹. Mice with increased concentrations of HSP90b had less symptomology and greater clearance of beta amyloid deposits through activation of PPARg signaling¹. HSP90b was shown to be upregulated by increasing concentrations of JuA in mice lacking HSP90b, which also led to less endothelial dysfunction¹. Lastly, HSP90a when downregulated in mice was found to increase pyroptosis⁵. Conclusion. HSP90 provides a possible mechanism by which dementia could therapeutically be targeted. Through the amelioration of upregulation of HSP90b, either directly or through the implementation of JuA, could provide a positive outcome for dementia patients if implemented during early stages. Additionally, HSP90a induced pyroptosis diminishment may provide a secondary means of therapeutic targeting, which could be beneficial for the outcome of patients with dementia symptoms.

1. Zhang M, Qian C, Zheng ZG, et al. Jujuboside A promotes Aβ clearance and ameliorates cognitive deficiency in Alzheimer’s disease through activating Axl/HSP90/PPARγ pathway. Theranostics. 2018;8(15):4262-4278. doi:10.7150/thno.26164
2. Rajani RM, Quick S, Ruigrok SR, et al. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Sci Transl Med. 2018;10(448):eaam9507. doi:10.1126/scitranslmed.aam9507
3. Baumann J, Tsao CC, Huang SF, Gassmann M, Ogunshola OO. Astrocyte-specific hypoxia-inducible factor 1 (HIF-1) does not disrupt the endothelial barrier during hypoxia in vitro. Fluids Barriers CNS. 2021;18(1):13. doi:10.1186/s12987-021-00247-2
4. Fujii N, McGarr GW, Hatam K, et al. Heat shock protein 90 does not contribute to cutaneous vasodilatation in older adults during heat stress. Microcirculation. 2019;26(6):e12541. doi:10.1111/micc.12541
5. Zhou Z, Li X, Qian Y, Liu C, Huang X, Fu M. Heat shock protein 90 inhibitors suppress pyroptosis in THP-1 cells. Biochem J. 2020;477(20):3923-3934. doi:10.1042/BCJ20200351