The distribution of p38(MAPK) in the sensorimotor cortex of a mouse model of Alzheimer’s disease

The p38 mitogen-activated protein kinase [p38(MAPK)] mediates responses to extracellular stressors. An increase in the phosphorylated form of p38(MAPK) [p-p38(MAPK)] has been associated with early events in Alzheimer disease (AD). Although most often associated with processes including apoptosis, inflammation and oxidative stress, p-p38(MAPK) also mediates beneficial physiological functions, such as cell growth, survival and phagocytosis of cellular pathogens. Amyloid plaques [β-amyloid aggregates] are a hallmark of AD-related pathology. As p38(MAPK) has been detected in the vicinity of senile plaques, we combined immunohistochemistry and stereological sampling to quantify the distribution of plaques and p-p38(MAPK)-immunoreactive (IR) cells in the sensorimotor cortex of 3-, 6- and 10-month-old TgCRND8 mice. This animal model expresses an aggressive nature of the AD-related human amyloid-β protein precursor (APP). It was confirmed by the appearance of both dense-core (thioflavin-S-positive) and diffuse plaques, even in the youngest mice. p-p38(MAPK)-IR cells were associated with both dense-core and diffuse plaques, but the expected age-dependent increase in the density of plaque-associated p-p38(MAPK)-IR cells was restricted to dense-core plaques. Furthermore, the density of dense-core plaque-associated p-p38(MAPK)-IR cells was inversely correlated with the size of the core within the given plaque, which supports a role for these microglia in restricting core growth. p-p38(MAPK)-IR cells were also observed throughout wildtype and TgCRND8 mouse cortical parenchyma, but the density of these non-plaque-associated cells remained constant, regardless of age or genotype. We conclude that the constitutive presence of p-p38(MAPK)-IR microglia in aging mouse brain is indicative of a longitudinal role for this kinase in normal brain physiology. Additionally, the majority of p-p38(MAPK)-IR cells were predominantly co-immunoreactive for the Macrophage-1 (CD11b/CD18) microglial marker, regardless of whether they were associated with plaques or localized to the parenchyma. We suggest that the facts that a pool of p-p38(MAPK)-IR microglia appears to restrict β-amyloid plaque core development and the non-pathological role of p-p38(MAPK) in parenchyma, needs to be considered when anticipating targeted p38(MAPK) therapeutics in the context of clinical AD