engleski

NLRP1 and ASC expression in Alzheimer's disease: correlation with neuropathological changes in the hippocampal formation

Aberrant immune response has been implicated in the pathogenesis of Alzheimer’s disease (AD), but it is not clear how it leads to neuronal dysfunction and cognitive decline. One of the possible mechanisms could be the overactivation of the inflammasomes. Those multiprotein complexes are mostly expressed in the myeloid lineage (including microglial cells), except the NLRP1 inflammasome that is primarily expressed in pyramidal neurons. Some polymorphisms of the NLRP1 gene have been associated with AD onset. We aimed to compare the expression of NLRP1 and ASC molecules in postmortem tissue of the different fields of the hippocampal formation in 12 AD and 12 control subjects. NLRP1 and ASC were visualized immunohistochemically. Semiquantitatively assessed NLRP1- and ASC-immunoreactivity was correlated with age, duration of the disease, and severity of characteristic neuropathological changes. The results showed that the expression of NLRP1 and ASC was higher in AD brains compared to controls, suggesting that NLRP1 inflammasome is more active in AD brain. Interestingly, the CA2/3 field was least vulnerable field to AD pathology, although it had the most abundant immunoreactivity for both markers. The moderately positive correlation between the number of neurofibrillary tangles (NFT) and NLRP1 expression (Spearman r=0.55, p=0.07) and statistically significant correlation between NFT number and ASC expression (Spearman r=0.73, p=0.009) suggest that increased NLRP1 and ASC expression might be associated with earlier neuroinflammatory changes. These changes were irrespective of age (Spearman r=-0.28) and disease duration (Spearman r=0.47). In conclusion, our preliminary findings on a relatively small number of AD and control postmortem samples confirmed the previous reports of increased NLRP1 expression in AD (Kaushal et al., Cell Death Differ., 2015 ; Saresella et. al., Mol. Neurodegener., 2016) and additionally revealed that NLRP1 and ASC expression patterns in the hippocampal formation of the neuropathologically-confirmed AD subjects positively correlate with the extent of neurofibrillary degeneration, but not the number of amyloid plaques. These findings warrant further investigations on the role of inflammasome in development of AD. Acknowledgements: Supported by the Croatian Science Foundation grant IP-2019-04- 3584 and the Centre of Excellence for Basic, Clinical, and Translational Neuroscience (project “Experimental and clinical research of hypoxic- ischemic damage in perinatal and adult brain” ; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund).

Alzheimer's disease ; hippocampal formation ; inflammasome ; microglial cells ; neuropathology

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