Stress‐Activated Protein Kinase/c‐Jun N‐Terminal Kinase Phosphorylates τ Protein

124

Neurofibrillary tangles (NFTs) are found in a wide range of neurodegenerative disorders, including Alzheimer's disease. The major component of NFTs is aberrantly hyperphosphorylated microtubule-associated protein tau. Because appropriate in vivo models have been lacking, the role of tau phosphorylation in NFTs formation has remained elusive. Here, we describe a new model in which adenovirus-mediated gene expression of tau, ⌬MEKK, JNK3, and GSK-3␤ in COS-7 cells produces most of the pathological phosphorylation epitopes of tau including AT100. Furthermore, this coexpression resulted in the formation of tau aggregates having short fibrils that were detergent-insoluble and Thioflavin-S-reactive. These results suggest that aberrant tau phosphorylation by the combination of these kinases may be involved in "pretangle," oligomeric tau fibril formation in vivo.Filamentous tau aggregates is the major component of neurofibrillary tangles (NFTs) 1 (1), the most common neuropathological hallmark in several neurodegenerative disorders, including Alzheimer's disease (AD). Discovery of the molecular mechanisms of NFT formation may provide more direct insight into the process of neurodegeneration in AD. NFTs consist of highly phosphorylated microtubule-associated protein tau that assembles to form fibrils with ␤-sheet structures within the cell body and dendrites of neurons (2, 3). Several in vitro studies reveal that the repeat domain of tau aggregates more readily than full-length tau (4, 5) and forms the core of tau fibrils in AD (6). Moreover, this aggregate formation is enhanced by the existence of a polyanion such as heparin (7,8) or by RNA (9) or fatty acids (10) in the absence of tau phosphorylation. However, these in vitro conditions may not be relevant to the mechanism underlying the formation of NFTs, because tau is always aberrantly hyperphosphorylated in AD. Therefore, it would seem necessary to consider the role of hyperphosphorylation of tau in the abnormal aggregation of filamentous tau.The assembly of phosphorylated tau was also observed during the presence of 4-hydoroxy-2-nonenal (11), a lipid peroxidation by-product of oxidative stress. Increased oxidative stress is reported to occur in AD (12-15). Interestingly, phospho-tau immunoreactive neurons are also stained positively with 8-hydroxy-oxyguanine, another marker for oxidative stress (16, 17). These results suggest that oxidative stress may, in part, trigger the formation of NFTs. If oxidative stress does participate in NFTs formation in AD, such stress can lead to the activation of kinases that phosphorylate tau and stimulate NFT formation. One such candidate kinase is stress-activated protein kinase/ c-Jun N-terminal kinase (SAPK/JNK), a member of the mitogen-activated protein kinase family that is activated by several kinase cascades. Recent studies, employing antibodies against paired helical filaments (PHFs), have reported that activated phospho-JNK co-localized in neurons displaying PHF immunoreactivities (18,19). Phospho-JNK was also shown to trans...

Section: Discussionsupporting

confidence: 91%

Aberrant Tau Phosphorylation by Glycogen Synthase Kinase-3β and JNK3 Induces Oligomeric Tau Fibrils in COS-7 Cells

Sato¹,

Tatebayashi²,

Akagi³

et al. 2002

124

“…7) and both endogenous and exogenously expressed Tau were phosphorylated. Although our study does not identify the kinase responsible for phosphorylation at Thr-231, Thr-231 is a known substrate for several kinases including glycogen synthase kinase-3␤ (37,65,66) and members of the MAPK family such as ERK, c-Jun N-terminal kinase (JNK), and p38 (67)(68)(69)(70). Because glycogen synthase kinase-3␤ is typically inactivated in response to NGF or EGF signaling (71), the phosphorylation of Tau at Thr-231 in the context of growth factor signaling is likely to be mediated by MAPK family members, leading to a positive feedback mechanism that would enhance signaling.…”

Section: Discussionmentioning

confidence: 87%

Tau Potentiates Nerve Growth Factor-induced Mitogen-activated Protein Kinase Signaling and Neurite Initiation without a Requirement for Microtubule Binding

Leugers¹,

Lee

2010

Microtubule-associated protein Tau is known to bind to and stabilize microtubules, thereby regulating microtubule dynamics. However, recent evidence has indicated that Tau can also interact with various components of intracellular signaling pathways, leading to the possibility that Tau might have a role in signal transduction. Here we provide evidence that during growth factor stimulation of neuronal cells, Tau has functions in advance of the neurite elongation stage. Using Tau-depleted neuronal cell lines, we demonstrate that Tau is required for neurite initiation in a manner that does not involve its microtubule binding function. In addition, we demonstrate that Tau potentiates AP-1 transcription factor activation in response to nerve growth factor (NGF). The effect of Tau on AP-1 activation is mediated through its ability to potentiate the activation of mitogen-activated protein kinase (MAPK), which occurs in response to both NGF and epidermal growth factor. Phosphorylation of Tau at Thr-231 also occurs in response to NGF and is required for Tau to impact on MAPK signaling, whereas the ability of Tau to bind to microtubules is not required. Together, these findings indicate a new functional role for Tau in early neuronal development independent of its established role in microtubule stabilization.Microtubule-associated proteins are a class of proteins that includes Tau, MAP2, and MAP4. These proteins are so named for their ability to bind to and stabilize microtubules, thereby contributing to the regulation of microtubule dynamics. Tau in particular has been extensively studied due to its prominent role in the pathogenesis of neurodegenerative diseases such as Alzheimer disease and the fronto-temporal dementias (reviewed in Refs. 1-4). In general, research into the physiological functions of Tau has focused on its interactions with microtubules. However, additional roles for Tau beyond those associated with microtubules have been suggested by numerous studies. We have previously demonstrated that the amino terminus of Tau, a domain not involved in microtubule binding, is associated with the plasma membrane and can affect nerve growth factor (NGF) 2 -induced neurite outgrowth (5). Also, neurite outgrowth was shown to require phosphorylation of Tau at Ser-262, a modification that reduces the ability of Tau to bind to microtubules (6). In addition, interactions between Tau and various signaling proteins such as Src, Fyn, Abl, the p85 subunit of phosphatidylinositol 3-kinase, phospholipase C␥, 14-3-3, and Grb2 have been described (7-12). Such findings suggest that non-microtubule-associated Tau species may be associated with signaling components at the plasma membrane during early neurogenesis and differentiation. Recent reports have also indicated that Tau can be linked to the increased expression of cell cycle proteins. Mice expressing human Tau in the absence of mouse Tau and mice expressing FTDP-17 mutant Tau were found to have abnormal expression of cell cycle proteins (13-15) and a cell culture model expres...

“…There are also three major pathologies in AD:amyloid ␤ plaques consisting mostly of aggregated A␤ (51), neurofibrillary tangles consisting mainly of hyperphosphorylated tau protein (52,53), and degenerating neurons (54). The three activated MAP kinases have been found to be associated with A␤ plaques, neurofibrillary tangles, and degenerating neurons (55)(56)(57)(58)(59)(60)(61)(62). Recently, a study was published indicating that activation of the three MAP kinase pathways happens in a defined temporal order (63).…”

Section: Discussionmentioning

confidence: 99%

Jun NH2-terminal Kinase (JNK) Interacting Protein 1 (JIP1) Binds the Cytoplasmic Domain of the Alzheimer's β-Amyloid Precursor Protein (APP)

Scheinfeld¹,

Roncarati²,

Vito³

et al. 2002

155

161

The familial Alzheimer's disease gene product amyloid ␤ precursor protein (APP) is sequentially processed by ␤-and ␥-secretases to generate the A␤ peptide. The biochemical pathway leading to A␤ formation has been extensively studied since extracellular aggregates of A␤ peptides are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of APP processing is unknown. Cleavage of APP by ␥-secretase releases, together with A␤, a COOH-terminal APP intracellular domain, termed AID. This peptide has recently been identified in brain tissue of normal control and patients with sporadic Alzheimer's disease. We have previously shown that AID acts as a positive regulator of apoptosis. Nevertheless, the molecular mechanism by which AID regulates this process remains unknown. Hoping to gain clues about the function of APP, we used the yeast two-hybrid system to identify interaction between the AID region of APP and JNK-interacting protein-1 (JIP1). This molecular interaction is confirmed in vitro, in vivo by fluorescence resonance energy transfer (FRET), and in mouse brain lysates. These data provide a link between APP and its processing by ␥-secretase, and stress kinase signaling pathways. These pathways are known regulators of apoptosis and may be involved in the pathogenesis of Alzheimer's disease. The amyloid ␤ (A␤)1 peptide is the principal component of amyloid plaques in the brain of Alzheimer's disease (AD) patients (1-3). A␤ is derived from APP by two sequential proteolytic events, one in the extracellular domain (␤-secretase cleavage) (4) and one in the transmembrane domain (␥-secretase cleavage) (5). APP processing has become firmly associated with the pathogenesis of AD with the identification of missense mutations in three genes associated with familial forms of AD (FAD). The FAD mutations identified to date are found in APP itself, and in two highly homologous genes now known as presenilin 1 and presenilin 2 (PS1, PS2) (6 -9). Presenilins are a key component of a multimolecular complex with ␥-secretase activity that contains at least one other recently identified protein named nicastrin (10 -16). A common feature of all FAD mutations is that they increase the generation of A␤ peptides (especially the A␤42 form, considered to be more pathogenic than the A␤40 peptide) by accelerating the rate of APP processing by either ␤-or ␥-secretase (5, 18 -20). In addition to the A␤ peptide which is mostly released from the cell, another peptide, AID, is released into the cytoplasm as a result of the ␥-secretase cleavage. Although the role of the A␤ peptide in the pathogenesis of AD has been extensively studied, only recently have there been reports as to the role of AID. AID-like peptides have recently been identified in human brains from normal controls and cases of sporadic AD (21). AID has also been implicated in the pathology of AD by data indicating that it can independently trigger apoptosis or enhance other apoptotic stimuli (21). This may represent the mechanism by wh...