The distribution of p38(MAPK) in the sensorimotor cortex of a mouse model of Alzheimer’s disease
Date
2011
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Masters
Abstract
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.
Description
Keywords
sensorimotor cortex, Alzheimer's disease, amyloid plaque, microglia, pp38
Citation
Degree
Master of Science (M.Sc.)
Department
Psychiatry
Program
Psychiatry