NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss
Abstract
:1. Introduction
2. Materials and Methods
2.1. Human Brain Tissue Autopsy Samples
2.2. Immunohistochemical and Immunofluorescent Staining
2.3. Analysis of Immunohistochemically Stained Sections
2.4. Unbiased Quantification of Neurons and Neurofibrillary Tangles
2.5. Statistical Analysis
3. Results
3.1. Analysis of NLRP1, ASC, cGSDMD, and Caspase-6 Immunostaining
3.2. Correlations between Immunohistochemical Markers of Inflammasome Activation
3.3. Correlation of Immunohistochemical Markers with the Age of the Subjects and Duration of Disease
3.4. Correlations between NLRP1 Inflammasome, Neurofibrillary Tangles, Number of Neurons, and Disease Duration
3.5. Age-Related Neuronal Loss and Number of Neurofibrillary Tangles
3.6. Assessment of Microglial Markers
3.6.1. IBA1
3.6.2. HLA-DR
3.6.3. CD68
3.7. Illustrations of the Most Significant Findings
3.8. Double-Labeling Experiments
3.8.1. Colocalization of NLRP1 with ASC, AT8, CD68, and HLA-DR
3.8.2. Colocalization of ASC with AT8
3.8.3. Colocalization of CASP-6 with AT8, CD68, and HLA-DR
4. Discussion
4.1. NLRP1 and ASC Immunoreactivity
4.2. Cleaved Gasdermin and Caspase-6 Immunoreactivity
4.3. Relationship of Inflammasome Activation with Neuron Loss, Neurofibrillary Pathology, and Other Indices of Neurodegeneration
4.4. Relationship of Inflammasome Activation with Microglial Markers IBA1, HLA-DR, and CD68
4.5. Limitation of the Study
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
4R tau | tau proteins with four microtubule-binding domain repeats |
AD | Alzheimer’s disease |
Aβ | amyloid β |
APP | amyloid precursor protein |
ASC | apoptosis-associated speck-like protein |
CA | cornu Ammonis |
CARD | caspase activation and recruitment domain |
CASP-1 | caspase-1 |
CASP-6 | caspase-6 |
CD68 | cluster of differentiation 68 |
CERAD | Consortium to Establish a Registry for Alzheimer’s Disease |
cGSDMD | cleaved gasdermin |
DSM-IV | Diagnostic and Statistical Manual of Mental Disorders, fourth edition |
HC | healthy controls |
HF | hippocampal formation |
hCA3 | hilar part of the CA3 field |
HLA-DR | Human Leukocyte Antigen–DR isotype |
IBA1 | Ionized calcium-binding adapter molecule 1 |
NFTs | neurofibrillary tangles |
NINCDS-ADRDA | National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association |
NLRs | NOD-like leucine-rich repeat receptors |
NLRP1 | nucleotide-binding domain and leucine-rich repeat-containing receptor family, pyrin domain-containing protein 1 |
NLRP3 | nucleotide-binding domain and leucine-rich repeat-containing receptor family, pyrin domain-containing protein 3 |
NN | number of neurons |
NOD | nucleotide-binding and oligomerization domain |
PBS | phosphate buffered saline |
rP | Pearson’s correlation coefficient |
rS | Spearman’s correlation coefficient |
SD | standard deviation |
SUB | subiculum |
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Case | HC | ||||
Age | Gender | Cause of Death | |||
HC1 | 59 | M | Car accident | ||
HC2 | 62 | F | Car accident | ||
HC3 | 68 | M | Car accident | ||
HC4 | 71 | F | Myocardial infarction | ||
HC5 | 75 | M | Car accident | ||
HC6 | 77 | F | Myocardial infarction | ||
HC7 | 81 | F | Myocardial infarction | ||
HC8 | 84 | F | Pulmonary embolism | ||
HC9 | 85 | F | Cardiovascular failure | ||
Case | AD | ||||
Age | Gender | Duration of the Disease (years) | Cause of Death | NINCDS-ADRDA Diagnosis | |
AD1 | 73 | F | 4 | Bronchopneumonia | Definitive AD |
AD2 | 73 | M | 7 | Bronchopneumonia | Definitive AD |
AD3 | 77 | M | 3.5 | Bronchopneumonia | Definitive AD |
AD4 | 80 | F | 5 | Bronchopneumonia | Definitive AD |
AD5 | 80 | F | 6 | Myocardial infarction | Definitive AD |
AD6 | 81 | M | 3 | Bronchopneumonia | Definitive AD |
AD7 | 83 | F | 5.5 | Cardiovascular failure | Probable AD |
AD8 | 84 | F | 3.5 | Cardiovascular failure | Definitive AD |
AD9 | 84 | F | 3.5 | Cardiovascular failure | Definitive AD |
AD10 | 88 | F | 4.5 | Carcinoma | Probable AD |
AD11 | 91 | F | 4 | Bronchopneumonia | Probable AD |
Case | hCA3 Counts | Area | CA2/3 Counts | Area | CA1 Counts | Area | SUB Counts | Area | Total Counts | Σ Area | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
N | A | G | C | mm2 | N | A | G | C | mm2 | N | A | G | C | mm2 | N | A | G | C | mm2 | N | A | G | C | mm2 | |
HC1 | 4 | 12 | 0 | 12 | 5981 | 23 | 26 | 0 | 1 | 3449 | 113 | 140 | 0 | 84 | 8421 | 0 | 0 | 0 | 0 | 0 | 140 | 178 | 0 | 97 | 17,852 |
HC2 | 86 | 92 | 32 | 108 | 7837 | 0 | 0 | 1 | 23 | 0 | 16 | 17 | 3 | 51 | 10,702 | 63 | 53 | 4 | 55 | 14,885 | 165 | 162 | 40 | 237 | 33,424 |
HC3 | 16 | 19 | 32 | 9 | 7738 | 38 | 24 | 47 | 11 | 11,277 | 30 | 50 | 50 | 9 | 17,299 | 67 | 32 | 22 | 55 | 12,825 | 151 | 125 | 151 | 84 | 49,139 |
HC4 | 52 | 38 | 10 | 13 | 3953 | 188 | 139 | 24 | 75 | 2302 | 159 | 100 | 4 | 35 | 10,149 | 279 | 121 | 2 | 44 | 10,065 | 678 | 398 | 40 | 167 | 26,468 |
HC5 | 54 | 95 | 81 | 98 | 7362 | 183 | 200 | 185 | 340 | 6829 | 113 | 109 | 252 | 230 | 22,223 | 57 | 155 | 43 | 55 | 23,678 | 407 | 559 | 561 | 723 | 60,092 |
HC6 | 35 | 17 | 12 | 7 | 4201 | 45 | 20 | 9 | 9 | 1803 | 28 | 18 | 3 | 14 | 13,001 | 65 | 173 | 48 | 70 | 10,486 | 173 | 228 | 72 | 100 | 29,490 |
HC7 | 6 | 149 | 17 | 43 | 4486 | 74 | 159 | 30 | 70 | 1596 | 44 | 131 | 11 | 22 | 12,506 | 96 | 160 | 41 | 53 | 9121 | 220 | 599 | 99 | 188 | 28,108 |
HC8 | 16 | 41 | 4 | 13 | 3445 | 32 | 149 | 8 | 78 | 1388 | 19 | 119 | 14 | 20 | 6647 | 20 | 96 | 0 | 15 | 15,423 | 87 | 405 | 26 | 126 | 26,903 |
HC9 | 73 | 83 | 7 | 13 | 5412 | 67 | 36 | 0 | 5 | 3916 | 69 | 26 | 0 | 16 | 14,360 | 34 | 42 | 0 | 24 | 14,239 | 243 | 187 | 7 | 58 | 37,926 |
AD1 | 58 | 109 | 15 | 114 | 6247 | 73 | 129 | 51 | 102 | 2162 | 28 | 39 | 14 | 124 | 6441 | 24 | 99 | 13 | 146 | 6131 | 183 | 376 | 93 | 486 | 20,980 |
AD2 | 60 | 278 | 48 | 90 | 3897 | 127 | 124 | 58 | 80 | 1180 | 104 | 36 | 10 | 141 | 4680 | 284 | 300 | 36 | 129 | 9659 | 575 | 738 | 152 | 440 | 19,416 |
AD3 | 7 | 123 | 26 | 33 | 4018 | 96 | 81 | 45 | 41 | 2619 | 16 | 32 | 6 | 70 | 11,055 | 44 | 60 | 13 | 10 | 11,419 | 163 | 296 | 90 | 154 | 29,111 |
AD4 | 88 | 74 | 23 | 44 | 12,189 | 200 | 113 | 8 | 50 | 2671 | 180 | 27 | 2 | 171 | 7269 | 179 | 119 | 0 | 170 | 15,626 | 647 | 333 | 33 | 435 | 37,754 |
AD5 | 38 | 54 | 10 | 23 | 7351 | 152 | 131 | 36 | 25 | 1571 | 79 | 100 | 38 | 207 | 7029 | 98 | 170 | 11 | 130 | 10,083 | 367 | 455 | 95 | 385 | 26,034 |
AD6 | 84 | 156 | 21 | 39 | 8899 | 148 | 121 | 7 | 39 | 2588 | 100 | 14 | 0 | 79 | 5571 | 132 | 142 | 9 | 40 | 7837 | 464 | 433 | 37 | 197 | 24,894 |
AD7 | 38 | 227 | 44 | 60 | 4881 | 141 | 278 | 60 | 69 | 2720 | 65 | 82 | 15 | 226 | 7956 | 257 | 146 | 8 | 97 | 7240 | 501 | 733 | 127 | 452 | 22,797 |
AD8 | 45 | 67 | 22 | 74 | 8738 | 151 | 78 | 17 | 29 | 3386 | 105 | 38 | 29 | 439 | 8296 | 67 | 29 | 12 | 210 | 6921 | 368 | 212 | 80 | 752 | 27,342 |
AD9 | 4 | 45 | 11 | 29 | 3622 | 19 | 88 | 44 | 35 | 1995 | 48 | 19 | 16 | 275 | 6168 | 6 | 74 | 14 | 180 | 7741 | 77 | 226 | 85 | 519 | 19,527 |
AD10 | 20 | 17 | 12 | 22 | 4356 | 187 | 84 | 27 | 61 | 4201 | 66 | 54 | 24 | 215 | 21,832 | 109 | 45 | 4 | 245 | 6501 | 382 | 200 | 67 | 543 | 36,890 |
AD11 | 32 | 140 | 23 | 63 | 7476 | 113 | 172 | 8 | 67 | 2562 | 87 | 52 | 5 | 25 | 6547 | 32 | 117 | 0 | 2 | 3276 | 264 | 481 | 36 | 157 | 19,862 |
Case | NLRP1 (Cells/mm2) | ASC (Cells/mm2) | GSDMD (Cells/mm2) | CASP-6 (Cells/mm2) |
---|---|---|---|---|
HC1 | 0.784 | 1.000 | 0.000 | 0.543 |
HC2 | 0.494 | 0.480 | 0.120 | 0.709 |
HC3 | 0.307 | 0.250 | 0.307 | 0.171 |
HC4 | 2.562 | 1.500 | 0.151 | 0.631 |
HC5 | 0.677 | 0.930 | 0.934 | 1.203 |
HC6 | 0.587 | 0.770 | 0.244 | 0.339 |
HC7 | 0.783 | 2.130 | 0.352 | 0.669 |
HC8 | 0.323 | 1.510 | 0.097 | 0.468 |
HC9 | 0.641 | 0.490 | 0.019 | 0.153 |
AD1 | 0.872 | 1.792 | 0.443 | 2.316 |
AD2 | 2.961 | 3.801 | 0.783 | 2.266 |
AD3 | 0.560 | 1.017 | 0.309 | 0.529 |
AD4 | 1.714 | 0.882 | 0.087 | 1.152 |
AD5 | 1.410 | 1.748 | 0.365 | 1.479 |
AD6 | 1.864 | 1.740 | 0.149 | 0.791 |
AD7 | 2.198 | 3.215 | 0.557 | 1.983 |
AD8 | 1.346 | 0.775 | 0.293 | 2.750 |
AD9 | 0.394 | 1.157 | 0.435 | 2.658 |
AD10 | 1.036 | 0.542 | 0.182 | 1.472 |
AD11 | 1.329 | 2.422 | 0.181 | 0.790 |
Case | hCA3 | CA2/3 | CA1 | SUB | Σ | ||||
---|---|---|---|---|---|---|---|---|---|
NN (106) | NFTs (106) | NN (106) | NFTs (106) | NN (106) | NFTs (106) | NN (106) | NFTs (106) | NFTs (106) | |
HC1 | 0.84 | 0 | 1.2 | 0 | 7.18 | 0 | 2.61 | 0 | 0 |
HC2 | 1.29 | 0 | 1.41 | 0 | 8.41 | 0 | 4.34 | 0 | 0 |
HC3 | 1.57 | 0 | 1.94 | 0 | 2.62 | 0 | 2 | 0 | 0 |
HC4 | 1.27 | 0 | 2.9 | 0 | 5.35 | 0 | 1.47 | 0 | 0 |
HC5 | 1.4 | 0 | 2.48 | 0 | 8.28 | 0 | 4.85 | 0.05 | 0.05 |
HC6 | 0.83 | 0 | 1.68 | 0 | 2.43 | 0 | 1.79 | 0.03 | 0.03 |
HC7 | 0.87 | 0 | 1.61 | 0 | 3.42 | 0 | 2.29 | 0 | 0 |
HC8 | 1.35 | 0 | 1.45 | 0 | 7.89 | 0.01 | 4.89 | 0 | 0 |
HC9 | 1.29 | 0 | 2.16 | 0 | 2.26 | 0 | 1.59 | 0 | 0 |
AD1 | 1 | 0.08 | 0.98 | 0.22 | 4.93 | 3.45 | 0.93 | 0.71 | 4.45 |
AD2 | 1.63 | 0.08 | 1.45 | 0.51 | 5.48 | 4.02 | 3.47 | 0.54 | 5.14 |
AD3 | 0.57 | 0.13 | 1.64 | 0 | 5 | 0.81 | 1.42 | 0.25 | 1.19 |
AD4 | 0.93 | 0.16 | 1.82 | 0.11 | 10.9 | 1.95 | 2.78 | 0.43 | 2.66 |
AD5 | 0.3 | 0 | 0.92 | 0.18 | 4.38 | 3.15 | 2.4 | 0.52 | 3.85 |
AD6 | 1.8 | 0.3 | 0.78 | 0.2 | 4.59 | 2.88 | 3.16 | 1.19 | 4.57 |
AD7 | 0.37 | 0 | 1 | 0 | 3.09 | 1.99 | 1.25 | 0.13 | 2.13 |
AD8 | 1.67 | 0.07 | 1.39 | 0.11 | 7.65 | 2.42 | 3.81 | 0.55 | 3.15 |
AD9 | 0.17 | 0.08 | 1.26 | 0 | 2.06 | 1.42 | 1.01 | 0.3 | 1.8 |
AD10 | 0.23 | 0 | 0.84 | 0.19 | 3.27 | 1.88 | 1.79 | 0.68 | 2.74 |
AD11 | 0.53 | 0.08 | 0.96 | 0.37 | 1.14 | 0.55 | 0.84 | 0.27 | 1.27 |
Case | hCA3 Counts | CA2/3 Counts | CA1 Counts | SUB Counts | Total Counts per Sample | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
I | H | C | I | H | C | I | H | C | I | H | C | I | H | C | |
HC1 | 3 | 3 | 3 | 2 | 3 | 2 | 0 | 2 | 2 | 1 | 2 | 2 | 6 | 10 | 9 |
HC2 | 3 | 2 | 2 | 3 | 2 | 3 | 2 | 3 | 1 | 3 | 2 | 1 | 11 | 9 | 7 |
HC3 | 2 | 0 | 1 | 2 | 0 | 2 | 2 | 0 | 1 | 1 | 0 | 1 | 7 | 0 | 5 |
HC4 | 2 | 0 | 1 | 2 | 0 | 1 | 2 | 0 | 2 | 3 | 0 | 2 | 9 | 0 | 6 |
HC5 | 2 | 2 | 2 | 1 | 2 | 2 | 0 | 2 | 1 | 0 | 2 | 1 | 3 | 8 | 6 |
HC6 | 2 | 2 | 2 | 1 | 3 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 7 | 9 | 8 |
HC7 | 0 | 1 | 2 | 1 | 0 | 2 | 1 | 0 | 1 | 0 | 2 | 3 | 2 | 3 | 8 |
HC8 | 3 | 0 | 2 | 2 | 0 | 2 | 2 | 0 | 1 | 2 | 1 | 2 | 9 | 1 | 7 |
HC9 | 2 | 0 | 3 | 1 | 0 | 2 | 2 | 0 | 2 | 2 | 0 | 2 | 7 | 0 | 9 |
AD1 | 0 | 0 | 3 | 0 | 2 | 2 | 0 | 1 | 4 | 0 | 1 | 3 | 0 | 4 | 12 |
AD2 | 2 | 1 | 4 | 3 | 1 | 3 | 3 | 2 | 4 | 3 | 1 | 4 | 11 | 5 | 15 |
AD3 | 0 | 1 | 3 | 2 | 0 | 3 | 1 | 2 | 4 | 0 | 2 | 3 | 3 | 5 | 13 |
AD4 | 2 | 1 | 3 | 3 | 0 | n.a. | 2 | 3 | 4 | 3 | 4 | 4 | 10 | 8 | 11 |
AD5 | 3 | 3 | 3 | 2 | 3 | 3 | 3 | 3 | 4 | 3 | 3 | 3 | 11 | 12 | 13 |
AD6 | 2 | 2 | 4 | 3 | 0 | 3 | 3 | 3 | 4 | 2 | 2 | 3 | 10 | 7 | 14 |
AD7 | 0 | 2 | 1 | 3 | 0 | 3 | 2 | 4 | 3 | 4 | 4 | 4 | 9 | 10 | 11 |
AD8 | 0 | 4 | 4 | 1 | 3 | 3 | 1 | 4 | 4 | 0 | 4 | 4 | 2 | 15 | 15 |
AD9 | 0 | 2 | 4 | 3 | 0 | 3 | 3 | 2 | 4 | 2 | 0 | 3 | 8 | 4 | 14 |
AD10 | 3 | 0 | 2 | 3 | 2 | 3 | 3 | 3 | 3 | 3 | 2 | 4 | 12 | 7 | 12 |
AD11 | 3 | 3 | 2 | 3 | 2 | 2 | 3 | 3 | 2 | 2 | 3 | 3 | 11 | 11 | 9 |
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Španić, E.; Langer Horvat, L.; Ilić, K.; Hof, P.R.; Šimić, G. NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss. Cells 2022, 11, 2223. https://doi.org/10.3390/cells11142223
Španić E, Langer Horvat L, Ilić K, Hof PR, Šimić G. NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss. Cells. 2022; 11(14):2223. https://doi.org/10.3390/cells11142223
Chicago/Turabian StyleŠpanić, Ena, Lea Langer Horvat, Katarina Ilić, Patrick R. Hof, and Goran Šimić. 2022. "NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss" Cells 11, no. 14: 2223. https://doi.org/10.3390/cells11142223