NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss

Abstract

Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression of NLRP1, ASC, cleaved gasdermin (cGSDMD), and active caspase-6 (CASP-6) proteins in each hippocampal subdivision (hilar part of CA3, CA2/3, CA1, subiculum) of postmortem tissue of 9 cognitively healthy controls (HC) and 11 AD patients whose disease duration varied from 3 to 7 years after the clinical diagnosis. The total number of neurons, along with the total number of neurofibrillary tangles (NFTs), were estimated in Nissl- and adjacent modified Bielschowsky-stained sections, respectively, using the optical disector method. The same 9 HC and 11 AD cases were additionally semiquantitatively analyzed for expression of IBA1, HLA-DR, and CD68 microglial markers. Our results show that the expression of NLRP1, ASC, and CASP-6 is present in a significantly greater number of hippocampal formation neurons in AD brains compared to controls, suggesting that the NLRP1 inflammasome is more active in the AD brain. None of the investigated inflammasome and microglial markers were found to correlate with the age of the subjects or the duration of AD. However, besides positive correlations with microglial IBA1 expression in the subiculum and with microglial CD68 expression in the CA1 field and subiculum in the AD group, the overall NLRP1 expression in the hippocampal formation was positively correlated with the number of NFTs, thus providing a causal link between neuroinflammation and neurofibrillary degeneration. The accumulation of AT8-immunoreactive phosphorylated tau proteins that we observed at nuclear pores of large pyramidal neurons of the Ammon’s horn further supports their role in the extent of neuronal dysfunction and degeneration in AD. This is important because unlike fibrillar amyloid-β deposits that are not related to dementia severity, total NFTs and neuron numbers in the hippocampal formation, especially in the CA1 field, are the best correlates of cognitive deterioration in both human brain aging and AD. Our findings also support the notion that the CA2 field vulnerability is strongly linked to specific susceptibilities to different tauopathies, including primary age-related tauopathy. Altogether, these findings contrast with reports of nonsignificant microglial activation in aged nonhuman primates and indicate that susceptibility to inflammasome activation may render the human brain comparatively more vulnerable to neurodegenerative changes and AD. In conclusion, our results confirm a key role of NLRP1 inflammasome in AD pathogenesis and suggest NLRP1 as a potential diagnostic marker and therapeutic target to slow or prevent AD progression.

Identification of inflammasome signaling proteins in neurons and microglia in early and intermediate stages of Alzheimer's disease

“…We sought to find if the number of neurons with neurofibrillary tangles alters between intermediate AD and low AD. A significant increase in the number of pTau positive neurons was seen in the intermediate cases compared to the low AD cases in the subiculum (p = 0.0006; Intermediate AD 64 2B,D,F). The increase in neurofibrillary counts exemplifies the extent of neurodegeneration occurring in specific hippocampal regions.…”

Metals in Alzheimer’s Disease

“…It is possible, however, that tau cleavage or folding occurs first, followed by phosphorylation and detachment from the microtubules [ 21 ]. In addition to amyloid and tau-related mechanisms, oxidative stress, neuroinflammation, mitochondria, lysosomes, neurovascular, and cell cycle dysfunction all play important roles in the pathological process of AD [ 22 , 23 , 24 , 25 ].…”

Microglial autophagy in Alzheimer’s disease and Parkinson’s disease

“…NLRP inflammasome plays a certain role in the pathogenesis of AD. In monocytes of AD patients, the mRNA and protein levels of NLRP3 are significantly increased ( Saresella et al, 2016 ), and NLRP1 is activated in the hippocampus of AD patients ( Španić et al, 2022 ). The abnormal Aβ and Tau induce inflammation through specific pathways involving MYD88 or NF-κB ( Yang et al, 2020 ; Barczuk et al, 2022 ), leading to the transcription of pro-IL-β and NLRP3 ( Lee J. H. et al, 2021 ; Leng and Edison, 2021 ).…”