The increased density of p38 mitogen-activated protein kinase-immunoreactive microglia in the sensorimotor cortex of aged TgCRND8 mice is associated predominantly with smaller dense-core amyloid plaques

Abstract

The role for phosphorylated p38 mitogen-activated protein kinase [p-p38(MAPK)] in β-amyloid plaque deposition [a hallmark of Alzheimer's disease (AD) pathology] remains ambiguous. 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. The aggressive nature of the AD-related human amyloid-β protein precursor expressed in these mice 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 of the sensorimotor cortex were predominantly co-immunoreactive for the Macrophage-1 (CD11b/CD18) microglial marker. These p-p38(MAPK)-IR microglia 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 microglia was restricted to dense-core plaques. Furthermore, the density of dense-core plaque-associated p-p38(MAPK)-IR microglia 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 microglia were also observed throughout wildtype and TgCRND8 mouse cortical parenchyma, but the density of these non-plaque-associated microglia 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. We suggest that this fact, as well as the fact that a pool of p-p38(MAPK)-IR microglia appears to restrict β-amyloid plaque core development, needs to be duly considered when ascribing functions for p38(MAPK) signalling in the AD brain.

Amyloid Pathology in Spinal Cord of the Transgenic Alzheimer's Disease Mice is Correlated to the Corticospinal Tract Pathway

“…Transection of the spinal cord or ablation of sensorimotor cortex reduced the formation of A␤ peptides in the affected regions further confirm the source of A␤ peptides. These results indicate that the sensorimotor cortex is highly susceptible to amyloid pathology [36]. This is consistent with a recent clinical study, which showed sensorimotor cortex is one of regions that is particularly vulnerable during the progression of AD in patients [37].…”

p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner

“…In some tissues, like bone marrow monocytes, an increase in the levels of p38 MAPK activation is associated with aging444555. In this study, we found that p38 MAPKs are highly activated in monocytes of older mice compared to young mice, suggesting that p38α may display a stronger effect on osteoclastogenesis in old mice than in young mice and as such, p38 ablation may show more robust effects on monocyte proliferation and differentiation.…”

“…S6), we suspect that the difference might be attributable to environmental changes in older mice. An increase in p38 MAPK activation in older mice has been reported in a few other tissues, which may reflect the accumulation of stress4445. Enhanced p38 MAPK activation may restrict monocyte proliferation in older mice to a greater extent than that in young mice; p38α deficiency may relieve this restriction and lead to greater expansion of monocytes in older mice than in young mice.…”

Postmitotic neurons develop a p21‐dependent senescence‐like phenotype driven by a DNA damage response

“…, 2009) 1:250; 53BP1 #305 (Nelson et al. , 2009) 1:1000 (Novus Biochemicals, Cambridge, UK); phosphor‐p38 #4631 (Chlan‐Fourney et al. , 2011) 1:50; 4‐HNE #HNEJ‐2 (Imai et al.…”