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Comparison of Neuroinflammation Induced by Hyperphosphorylated Tau Protein Versus Ab42 in Alzheimer’s Disease

Mol Neurobiol. 2023 Dec 18. doi: 10.1007/s12035-023-03822-w. Online ahead of print.


Both neurofibrillary tangles and senile plaques are associated with inflammation in Alzheimer’s disease (AD). Their relative degree of induced neuroinflammation, however, is not well established. Mouse models of AD that expressed either human Aβ42 (n = 7) or human hyperphosphorylated tau protein alone (n = 3), wild type (n = 10), and human AD samples (n = 29 with 18 controls) were studied. The benefit of using mouse models that possess only human tau or amyloid-b is that it allows for the individual evaluation of how each protein affects neuroinflammation, something not possible in human tissue. Three indicators of neuroinflammation were examined: TLRs/RIG1 expression, the density of astrocytes and microglial cells, and well-established mediators of neuroinflammation (IL6, TNFα, IL1β, and CXCL10). There was a statistically significant increase in neuroinflammation with all three variables in the mouse models with human tau only as compared to human Aβ42 only or wild-type mice (each at p < 0.0001). Only the Aβ42 5xFAD mice (n = 4) showed statistically higher neuroinflammation versus wild type (p = 0.0030). The human AD tissues were segregated into Aβ42 only or hyperphosphorylated tau protein with Aβ42. The latter areas showed increased neuroinflammation with each of the three variables compared to the areas with only Aβ42. Of the TLRs and RIG-1, TLR8 was significantly elevated in both the mouse model and human AD and only in areas with the abnormal tau protein. It is concluded that although Aβ42 and hyperphosphorylated tau protein can each induce inflammation, the latter protein is associated with a much stronger neuroinflammatory response vis-a-vis a significantly greater activated microglial response.

PMID:38105410 | DOI:10.1007/s12035-023-03822-w

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