Increased tau Phosphorylation on Mitogen-Activated Protein Kinase Consensus Sites and Cognitive Decline in Transgenic Models for Alzheimer's Disease and FTDP-17: Evidence for Distinct Molecular Processes Underlying tau Abnormalities

Abstract

Abnormal tau phosphorylation occurs in several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here, we compare mechanisms of tau phosphorylation in mouse models of FTDP-17 and AD. Mice expressing a mutated form of human tau associated with FTDP-17 (tau V337M ) showed age-related increases in exogenous tau phosphorylation in the absence of increased activation status of a number of kinases known to phosphorylate tau in vitro. In a "combined" model, expressing both tau V337M and the familial amyloid precursor protein AD mutation APP V717I in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to "single" tau V337M mice. These effects were concomitant with increased activation status of mitogen-activated protein kinase (MAPK) family members (extracellular regulated kinases 1 and 2, p38, and c-Jun NH 2 -terminal kinase) but not glycogen synthase kinase-3␣␤ or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APP V717I -CT100 transgene expression as near identical changes were observed in single APP V717I -CT100 mice. Age-dependent deficits in memory were also associated with tau V337M and APP V717I -CT100 expression. The data reveal distinct routes to abnormal tau phosphorylation in models of AD and FTDP-17 and suggest that in AD, tau irregularities may be linked to processing of APP C-terminal fragments via specific effects on MAPK activation status.

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

“…These observations agree with the concept that amyloid precursor proteins, not amyloid fibrils, cause organ dysfunction and contribute to the pathophysiology and progression in various amyloid-related diseases (7,8). Among the multiple key mediators involved in the regulation of redox status, stress-responsive p38 mitogen-activated protein kinases (MAPK) have been reported to be activated in other types of amyloid disease such as Alzheimer's disease (9)(10)(11)(12). Our prior findings have implicated oxidative stress in AL-LC-induced cellular dysfunction.…”

Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes

“…GSK-3␤ (Ser 9) is phosphorylated in response to insulin and IGF via phospho-Akt downstream in the phosphatidylinositol 3 kinase pathway and inhibits GSK-3␤. Here we demonstrated impaired phospho-Akt and GSK-3␤ (Ser 9), indirectly suggesting disinhibition of GSK-3␤, which is a prime candidate for hyperphosphorylation of cleaved (28,34,49,50), as demonstrated here in type 2 diabetic rats.…”

“…Despite the fact that insulin signaling appeared to be affected to similar extents in the two models, although for different reasons, the phospho-abnormalities were significantly more expressed in the type 2 model, suggesting that additional factors must be considered. Other so-called "-kinases" include cyclin-dependent kinases (cdk 5), mitogen-activated protein kinase family members, extracellular regulated kinase 1/2, and p38 and c-jun NH 2 -terminal kinase (34). The negative regulation of phosphorylation by O-G1cNAcylation due to deficient brain glucose uptake has been invoked in Alzheimer's disease (35).…”

“…We have previously demonstrated significant apoptotic stresses affecting hippocampal neurons in the same diabetic models (33). Isoforms of the protein are highly susceptible to phosphorylation by several serine/threonine kinases such as mitogen-activated protein kinase, cdk5, and GSK-3␤ (32,34,47,48), of which the latter appears to play a prominent role (28,32,48,49). GSK-3␤ (Ser 9) is phosphorylated in response to insulin and IGF via phospho-Akt downstream in the phosphatidylinositol 3 kinase pathway and inhibits GSK-3␤.…”

Diabetes and Alzheimer's Disease - Is There a Connection?

“…Recent research has implicated hyperglycemia, insulin-resistance and impaired insulin and insulin-like growth factor-1 (IGF-1) signaling with activation of so-called stress (or tau) kinases as mechanisms in the production of phosphorylated tau, a characteristic hallmark of AD [17][18][19]. Less attention has been devoted to the possible role of hypercholesterolemia and its role in APP metabolism, abnormal Aβ handling and deposition, the second characteristic hallmark of AD.…”