Activation of p38 Kinase Links Tau Phosphorylation, Oxidative Stress, and Cell Cycle-Related Events in Alzheimer Disease

Abstract

The temporal association between oxidative stress and the hallmark pathologies of Alzheimer disease (AD) demonstrates that oxidative stress is among the earliest events in the disease. Nonetheless, neither the consequences of oxidative stress nor how oxidative stress relates to other pathological features of the disease are clear at this point. To begin to address these issues, we investigated p38 kinase, which is induced by oxidative stress, in the pathogenesis of AD. In hippocampal and cortical brain regions of individuals with AD, p38 is exclusively localized in association with neurofibrillar pathology. By marked contrast, these brain regions exhibit a low level of diffuse p38 staining in the neuronal cytoplasm in controls. We found a complete overlap of the immunostaining profiles of p38 and tau-positive neurofibrillary pathology and that the majority of p38 was activated in AD neurons, both of which support an association of p38 with the disease process. Moreover, the finding that PHF-tau co-immunoprecipitates with p38, and that p38 co-purifies with PHF-tau, strongly suggests that they are physically associated in vivo. Since p38 is also implicated in cell cycle regulation, our findings provide a link between the cell cycle re-entrant phenotype, cytoskeletal phosphorylation and oxidative stress in AD.

Mitochondrial Abnormalities in Alzheimer's Disease

“…Other changes of AD could very well be linked to mitochondria because blockage of mitochondrial energy production shifts amyloid ␤-protein precursor metabolism to the production of more amyloidgenic forms of amyloid-␤ (Gabuzda et al, 1994), induces the production of A68 antigen (Blass et al, 1990), and activates the mitogen-activated protein kinase pathway (Luo et al, 1997;Perry et al, 1999;Zhu et al, 2000Zhu et al, , 2001, all features of AD.…”

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

“…Hamster brain tissue was fixed for 24 h before 6‐μm‐thick slices were consecutively sectioned as described previously (Zhu et al ., 2000). Ten prion and ten control animals were sacrificed in this experiment.…”

“…Immunohistochemistry staining of the brain sections for mitochondria using anti‐COX IV antibodies was performed according to the protocol as described previously by Zhu et al . (2000). The stained tissue sections were examined under an Olympus microscope.…”

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

“…A␤ and glutamate have each been shown to activate p38 MAPK in cultured neurons by increasing reactive oxygen species (16,17), and the A␤-triggered microglial release of inflammatory mediators, especially IL-1␤, is hypothesized to activate neuronal p38 . p38␣ MAPK mediates A␤-initiated microglial inflammatory activation (21, 22), phosphorylates Tau protein in neurons (20,23,24), and mediates A␤-induced synaptic impairment in the cultured hippocampal slice (25). However, no experiments have yet elucidated whether p38 MAPK phosphorylates BACE1 and regulates A␤ generation.…”