Biomedical subjects

Jin-Jing Pei

Publications and source records attributed to Jin-Jing Pei.

18 recordsLinked to original sources

PubMed2006

Assessments of the accumulation severities of amyloid beta-protein and hyperphosphorylated tau in the medial temporal cortex of control and Alzheimer's brains.

Alzheimer's disease (AD) is characterized neuropathologically by neuritic plaques (NPs), and neurofibrillary tangles (NFTs). So far, the following key issues are not yet answered to the disease: (1) the accumulation degrees of three Abeta variants, and tau phosphorylation epitopes in AD as compared to control; (2) the correlation degrees of levels of three Abeta variants with different tau phosphorylation epitopes; (3) the correlation degrees of levels of three Abeta variants and different tau phosphorylation epitopes with Braak and CERAD staging systems. To address these issues, levels of Abeta40, Abeta42, and Abeta43, and phosphorylated tau were assessed by dot blots in homogenates of the medial temporal cortex from AD and control brains in the present study. These data implied different roles of tau phosphorylation epitopes in formation of NFTs, and in this process, Abeta might play a key role. Assessments of levels of these abnormal proteins by dot blots may serve as a useful complement to the morphological evaluations in diagnosis of AD.

Aged↗

PubMed2005

P70 S6 kinase mediates tau phosphorylation and synthesis.

Currently, we found that the 70-kDa p70 S6 kinase (p70S6K) directly phosphorylates tau at S262, S214, and T212 sites in vitro. By immunoprecipitation, p-p70S6K (T421/S424) showed a close association with p-tau (S262 and S396/404). Zinc-induced p70S6K activation could only upregulate translation of total S6 and tau but not global proteins in SH-SY5Y cells. The requirement of p70S6K activation was confirmed in the SH-SY5Y cells that overexpress wild-type htau40. Level of p-p70S6K (T421/S424) was only significantly correlated with p-tau at S262, S214, and T212, but not T212/S214, in Alzheimer's disease (AD) brains. These suggested that p70S6K might contribute to tau related pathologies in AD brains.

Alzheimer Disease↗

PubMed2005

PTEN levels in Alzheimer's disease medial temporal cortex.

Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a dual (protein tyrosine and lipid) phosphatase one of the functions of which is to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate to phosphatidylinositol-3,4-biphosphate thereby inhibiting phosphoinositide-dependent kinase activation of the cell survival kinase Akt. Akt activity is up regulated in Alzheimer's disease (AD) brain in parallel to the progression of neurofibrillary pathology. The present study determined whether altered expression of PTEN occurs in Alzheimer's disease brain. Western immunoblotting revealed no significant changes of PTEN protein levels in nuclear and membrane fractions of medial temporal cortex from a series of Alzheimer's disease and control cases. Similarly, no changes in PTEN protein levels, as determined by dot-blotting, were seen in temporal cortex homogenates from a separate series of Alzheimer's disease and control brains. A small but significant decrease in the levels of Ser(380) p-PTEN was seen in homogenates of Alzheimer's disease temporal cortex. Immunohistochemistry revealed PTEN immunoreactivity in a number of brain structures including neurons, capillaries and structures resembling oligodendrocytes and astrocytes. The majority of temporal cortex pyramidal neurons (93-100%) were PTEN immunopositive. The Alzheimer's disease cases had significantly lower numbers of total ( approximately 12% loss, P<0.02) and PTEN immunopositive ( approximately 15% loss, P<0.01) pyramidal neurons as compared to the control cases.

Aged↗

PubMed2005

Acute anoxia induces tau dephosphorylation in rat brain slices and its possible underlying mechanisms.

Abnormal phosphorylation of microtubule-associated protein tau plays a critical role in Alzheimer's disease (AD), together with a distinct decrease of energy metabolism in the affected brain regions. To explore the effect of acute energy crisis on tau phosphorylation and the underlying mechanisms, we incubated rat brain slices in artificial cerebrospinal fluid (aCSF) at 37 degrees C with or without an oxygen supply, or in aCSF with low glucose concentrations. Then, the levels of total, phosphorylated and unphosphorylated tau, as well as the activities and levels of protein phosphatase (PP)-1, PP-2A, glycogen synthase kinase 3 (GSK-3), extracellular signal-regulated protein kinase (ERK) and C-jun amino terminal kinase (JNK), were measured. It was found, unexpectedly, that tau was significantly dephosphorylated at Ser396/Ser404 (PHF-1), Ser422 (R145), Ser199/Ser202 (Tau-1), Thr181 (AT270), Ser202/Thr205 (AT8) and Thr231 (AT180) by acute anoxia for 30 min or 120 min. The activity of PP-2A and the level of dephosphorylated PP-2A catalytic subunit at tyrosine 307 (Tyr307) were simultaneously increased. The active forms of ERK1/2 and JNK1/2 were decreased under anoxic incubation. The PP-2A inhibitor, okadaic acid (OA, 0.75 microm), completely prevented tau from acute anoxia-induced dephosphorylation and restored the active forms of ERK1/2 and JNK1/2 to the control level. The activities and protein levels of GSK-3 and PP-1 showed no change during acute anoxia. These data suggest that acute anoxia induces tau dephosphorylation, and that PP-2A may play a key role in tau dephosphorylation induced by acute anoxia.

Acute Disease↗

PubMed2005

Zinc induces neurofilament phosphorylation independent of p70 S6 kinase in N2a cells.

Hyperphosphorylated neurofilaments are a part of neurofibrillary tangles in Alzheimer's disease brains. Zinc has been shown to be increased in the brain areas heavily affected by Alzheimer pathologies. Zinc could induce tau hyperphosphorylation in SH-SY5Y and N2a cells, and tau phosphorylation may be mediated by p70 S6 kinase activation. Many of the tau kinases can also phosphorylate neurofilaments, and in this study we wanted to see whether neurofilament phosphorylation is regulated by p70 S6 kinase in N2a cells. We found that zinc induces rapamycin-dependent p70 S6 kinase phosphorylation at Thr421/Ser424 and Thr389, and rapamycin-independent phosphorylation of neurofilaments at the SMI34 epitope. Although zinc could induce cell proliferation and cell growth, and increased phosphorylation of neurofilaments, only cell growth appeared to be related to p7056kinase activation.

Antibiotics, Antineoplastic↗

PubMed2005

Zinc-induced anti-apoptotic effects in SH-SY5Y neuroblastoma cells via the extracellular signal-regulated kinase 1/2.

Zinc levels are increased in brain areas severely affected by Alzheimer's disease (AD) pathologies. Zinc has both protective and neurotoxic properties and can stimulate both phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Several kinases related to these pathways including protein kinase B (PKB), p70 S6 kinase (p70S6K), and extracellular signal-regulated kinase 1/2 (ERK1/2) are known cell survival factors and are overactivated in neurons bearing neurofibrillary tangles (NFTs) in AD. The present study aimed to determine whether anti-apoptotic effects of zinc are mediated via these signaling pathways. Zinc was used to treat SH-SY5Y neuroblastoma cells and effects investigated in relation to PKB, p70S6K, and ERK1/2 in the absence and presence of the pro-apoptotic agent staurosporine (STS). Cell damage was evaluated by measuring levels of DNA fragmentation as well as the WST-1 assay for cell viability. Results indicated that: (1) treatment with high doses of zinc (>/=400 microM) for short time periods (</=2 h) gave rise to increased levels of DNA fragments, increased cell membrane permeability, and reduced mitochondria membrane potential; (2) treatment with 100 microM zinc for >2 h reversed an increased DNA fragmentation due to U0126 inhibition of ERK1/2; (3) increased DNA fragmentation due to STS could be protected against by 100 microM zinc; (4) the protective effects of 100 microM zinc on STS-induced DNA fragmentation could be partially reversed by U0126. These results indicate that a zinc-induced anti-apoptotic response in SH-SY5Y cells likely occurs through ERK1/2.

Apoptosis↗

PubMed2005

Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3beta in SH-SY5Y neuroblastoma cells.

We have previously reported an aberrant accumulation of activated protein kinase B (PKB), glycogen synthase kinase (GSK)-3beta, extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38 and p70 S6 kinase (p70S6K) in neurons bearing neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). However, the mechanism by which these tau candidate kinases are involved in the regulation of p70S6K and GSK-3beta phosphorylation is unknown. In the current study, 100 microM zinc sulfate was used, and influences of various components of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on p70S6K and GSK-3beta phosphorylation have been investigated in serum-deprived SH-SY5Y neuroblastoma cells. We found that zinc could induce an increase of phosphorylated (p) p70S6K, p-PKB, p-GSK-3beta, p-ERK1/2, p-JNK and p-p38, especially in long-term treatment (4-8 h). Treatment with different inhibitors including rapamycin, wortmannin, LY294002, and U0126, and their combinations, indicated that phosphorylation of p70S6K and GSK-3beta is regulated by rapamycin-dependent, PI3K and MAPK pathways. Furthermore, phosphorylation of p70S6K and GSK-3beta affected levels of tau unphosphorylated at the Tau-1 site and phosphorylated at the PHF-1 site, and p70S6K phosphorylation affected the total tau level. Thus, 100 microM zinc might activate PKB, GSK-3beta, ERK1/2, JNK, p38 and p70S6K, that are consequently involved in tau changes in SH-SY5Y cells.

Analysis of Variance↗

PubMed2005

Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain.

The pathogenesis of formation of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains is unknown. One of the possibilities might be that translation of tau mRNA is aberrantly regulated in AD brains. In the current study, levels of various translation control elements including total and phosphorylated (p) forms of mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), eukaryotic elongation factor 2 (eEF2), and eEF2 kinase were investigated in relationship with tau in homogenates of the medial temporal cortex from 20 AD and 10 control brains. We found that levels of p-mTOR (Ser2481), and p-4E-BP1 (Thr70 and Ser65) dramatically increase in AD, and are positively significantly correlated with total tau and p-tau. Levels of p-eEF2K were significantly increased, and total eEF2 significantly decreased in AD, when compared to controls. The changes of p-mTOR (2481), p-4E-BP1, and p-eEF2 were immunohistochemically confirmed to be in neurons of AD brains. This suggested that there are obvious abnormalities of elements related with translation control in AD brain and their aberrant changes may up-regulate the translation of tau mRNA, contributing to hyperphosphorylated tau accumulation in NFT-bearing neurons.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain.

Eukaryotic translation factor 4E (eIF4E) plays a key role in regulating protein translation. It was thought that in order to maintain neuronal functions, tau protein is continuously generated to compensate those being hyperphosphorylated and compromised in its ability to promote and maintain microtubule assembly in Alzheimer's disease. If eIF4E is involved in tau mRNA translation, level of eIF4E phosphorylation should be changed. In the current study, we found a dramatic increase of phosphorylated eIF4E in Alzheimer's disease, especially in those cases with late stages of neurofibrillary changes. Level of eIF4E phosphorylation is significantly correlated with total- and Alzheimer hyperphosphorylated taus. These data suggest that the increase of eIF4E phosphorylation is involved in formation of Alzheimer neurofibrillary changes.

Aged↗

PubMed2003

Effect of amyloid precursor protein 17mer peptide on microtubule structure and tau protein hyperphosphorylation in hippocampal neurons of experimental diabetic mice.

The objective of this study was to investigate whether microtubular structure changes and tau protein hyperphosphorylation exist in hippocampal neurons of experimental diabetic mice, and to study the effect of amyloid precursor protein 17mer peptide. The results showed that the microtubules of hippocampal neurons of diabetic mice manifested prominent signs of fragmentation and dissolution, tau protein is hyperphosphorylated at Ser 199/Thr 202 sites, enzymes related to the phosphorylation and dephosphorylation of tau protein were diminished. The administration of amyloid precursor protein 17mer peptide could ameliorate the foregoing changes in diabetic mice. These results indicated that protein synthesis in the brain tissue of diabetic mice decreased. Amyloid precursor protein 17mer peptide acted as a neuroprotective agent that globally alleviates the disturbances due to impaired energy metabolism in diabetic mice.

Amyloid beta-Protein Precursor↗

PubMed2003

Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease.

In Alzheimer's disease (AD) brain the activity of protein phosphatase (PP)-2A is compromised and that of the extracellular signal-regulated protein kinase (ERK1/2) of the mitogen-activated protein kinase (MAPK) family, which can phosphorylate tau, is up-regulated. We investigated whether a decrease in PP-2A activity could underlie the activation of these kinases and the abnormal hyperphosphorylation of tau. Rat brain slices, 400-microm-thick, kept under metabolically active conditions in oxygenated (95% O(2), 5% CO(2)) artificial CSF were treated with 1.0 micromol/L okadaic acid (OA) for 1 hour at 33 degrees C. Under this condition, PP-2A activity was decreased to approximately 35% of the vehicle-treated control slices, and activities of PP-1 and PP-2B were not affected. In the OA-treated slices, we observed a dramatic increase in the phosphorylation/activation of ERK1/2, MEK1/2, and p70 S6 kinase both immunohistochemically and by Western blots using phosphorylation-dependent antibodies against these kinases. Treatment of 6-microm sections of the OA-treated slices with purified PP-2A reversed the phosphorylation/activation of these kinases. Hyperphosphorylation of tau at several abnormal hyperphosphorylation sites was also observed, as seen in AD brain. These results suggest 1) that PP-2A down-regulates ERK1/2, MEK1/2, and p70 S6 kinase activities through dephosphorylation at the serine/threonine residues of these kinases, and 2) that in AD brain the decrease in PP-2A activity could have caused the activation of ERK1/2, MEK1/2, and p70 S6 kinase, and the abnormal hyperphosphorylation of tau both via an increase in its phosphorylation and a decrease in its dephosphorylation.

Alzheimer Disease↗

PubMed2003

Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease.

The ribosomal S6 protein kinase p70 S6 kinase is known for its role in modulating cell-cycle progression, cell size, and cell survival. In response to mitogen stimulation, p70 S6 kinase activation up-regulates ribosomal biosynthesis and enhances the translational capacity of the cell. In Alzheimer's disease (AD), there is a marked increase in total tau protein in the form of abnormally hyperphosphorylated tau (PHF-tau) in neurons with neurofibrillary tangles (NFTs). In the present study, we investigated whether p70 S6 kinase activation is associated with PHF-tau accumulation in AD. By immunohistochemistry, we found that the levels of phosphorylated p70 S6 kinase (at Thr389 or at Thr421/Ser424) were increased in accordance with the progressive sequence of neurofibrillary changes according to Braak's criteria. Confocal microscopy showed that in AD brain, phosphorylated p70 S6 kinase appeared especially in neurons that are known to later develop NFTs. This pattern of neurons showed dot-like structures of phosphorylated p70 S6 kinase and hyperphosphorylated tau, which partially correlated with rab5 (endosome marker), lamp-1 (lysosome marker), and ubiquitin (ubiquitin-proteasomal system marker). By indirect enzyme-linked immunosorbent assay, phosphorylated p70 S6 kinase (Thr389 or Thr421/Ser424), total tau, and PHF-tau were found to be significantly increased in AD brain as compared to control cases. The levels of total p70 S6 kinase and p70 S6 kinase phosphorylated at Thr421/Ser424 showed significant correlations with the levels of both total tau and PHF-tau. Regression analyses revealed a significant dependence of total tau or PHF-tau on p70 S6 kinase phosphorylated at Thr421/Ser424 rather than at Thr389. The levels of ribosomal protein S6 as well as the levels of markers for the proteolytic system were also significantly increased in AD as compared to control brain. Using a SH-SY5Y neuroblastoma cell model, we found that 100 micro mol/L zinc sulfate could induce p70 S6 kinase phosphorylation and activation, in particular at Thr421/Ser424. This up-regulation of the activated kinase resulted in an increased expression and phosphorylation of tau. Pretreatment of cells with rapamycin (an inhibitor of FRAP/mTOR which is the immediate upstream kinase of the p70 S6 kinase) attenuated the effects induced by zinc. In primary cultured neurons of rat cortical cortex, zinc sulfate treatment could repeat p70 S6 kinase phosphorylation and activation at Thr421/Ser424, followed by increased expression and phosphorylation of tau. Taken together, these data suggest that activated p70 S6 kinase could mediate an up-regulation of tau translation. The partial co-localization of phosphorylated p70 S6 kinase with rab5, lamp-1 and ubiquitin, or PHF-tau with ubiquitin suggests that the activated proteolytic system might not be sufficient to degrade the over-produced and over-phosphorylated tau protein. A p70 S6 kinase modulated up-regulation of tau translation might contribute to PHF-tau accumulation in neurons with neurofibrillary changes.

Aged↗

PubMed2003

Alzheimer neurofibrillary degeneration: therapeutic targets and high-throughput assays.

Neurofibrillary degeneration has primary and pivotal involvement in the pathogenesis of Alzheimer disease (AD) and other tauopathies. The inhibition of this lesion offers a promising therapeutic approach. The microtubule- associated protein (MAP) tau is abnormally hyperphosphorylated in the brain of patients with AD, and in this form it is the major protein subunit of paired helical filaments/neurofibrillary tangles (PHF/NFT). The abnormal tau that is polymerized into PHF/NFT is apparently inert and has no effect on microtubule assembly in vitro. The cytosolic abnormally hyperphosphorylated tau from AD brain, the AD P-tau, does not promote in vitro microtubule assembly but, instead, sequesters normal tau, MAP1, and MAP2 and inhibits microtubule assembly. The AD P-tau readily self-assembles in vitro into tangles of PHF/straight filaments, and this self-assembly requires the abnormal hyperphosphorylation of this protein. Although, to date, an up-regulation of the activity of a tau kinase has not been established, the activity of phosphoseryl/ phosphothreonyl protein phosphatase (PP)-2A, which regulates the phosphorylation of tau, is compromised in AD brain. Thus, modulation of the activities of pp-2A and one or more tau kinases and inhibition of the sequestration of normal MAPs by AD P-tau offer promising therapeutic opportunities to inhibit neurofibrillary degeneration and the diseases characterized by this lesion. Development of high-throughput screening assays for potential drugs aimed at these therapeutic targets is currently under way.

Alzheimer Disease↗

PubMed2002

Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease.

The abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) has been proposed to involve the extracellular-signal-regulated protein kinase (ERK) of the mitogen-activated protein (MAP) kinase family. ERK is phosphorylated and thereby activated by MAP kinase kinase (MEK). In the present study, we determined the intracellular and regional distribution of the active forms of both MEK1/2 and ERK1/2, i.e. p-MEK1/2 and p-ERK1/2 in the entorhinal, hippocampal, and temporal cortices of 49 brains staged for neurofibrillary changes according to Braak and Braak's protocol. We found that p-MEK1/2 and p-ERK1/2 were present in the initial stages of neurofibrillary degeneration in the projecting neurons in the transentorhinal region, and extended into other brain regions co-incident with the progressive sequence of neurofibrillary changes up to and including Braak stage VI. It appeared that the accumulation of p-MEK1/2 and p-ERK1/2 was initiated in the cytoplasm of pretangle neurons in varying size granules, which grew into large aggregates co-existing with the progressive development of neurofibrillary tangles. Accumulation of p-MEK1/2 and p-ERK1/2 was found in cases with stages I-III neurofibrillary degeneration, which were devoid of amyloid deposition. These data provide direct in situ evidence consistent with the possible involvement of MAP kinase pathway in the hyperphosphorylation of tau and the presence of this lesion before deposition of beta-amyloid in AD.

Adult↗

PubMed2002

Role of protein kinase B in Alzheimer's neurofibrillary pathology.

Protein kinase B (PKB) is an important intermediate in the phosphatidylinositol-3 kinase signaling cascade that acts to phosphorylate glycogen synthase kinase-3 (GSK-3) at its serine 9 residue, thereby inactivating it. Activated GSK-3 has been previously shown to be preferentially associated with neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. In the present study, we performed immunohistochemistry with an antibody to the active form of PKB in brains with different stages of neurofibrillary degeneration. We found that the amount of activated PKB (p-Thr308) increased in correlation to the progressive sequence of AT8 immunoreactivity and neurofibrillary changes assessed according to Braak's criteria. By confocal microscopy, activated PKB (p-Thr308) was found to appear in particular in neurons that are known to later develop NFTs in AD. Western blotting showed that activated PKB was increased by more than 50% in the 16,000- g supernatants of AD brains as compared with normal aged and Huntington's disease controls. This increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site. These studies suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.

Adult↗

PubMed2002

Up-regulation of cell division cycle (cdc) 2 kinase in neurons with early stage Alzheimer's disease neurofibrillary degeneration.

The major component of Alzheimer's disease (AD) neurofibrillary tangles (NFTs) is abnormally hyperphosphorylated tau aggregated as paired helical filaments (PHFs). Cell division cycle (cdc) 2 kinase is one of the main candidate kinases that phosphorylates normal tau in vitro at several sites seen in PHF-tau. Using brains staged according to Braak and Braak criteria, we investigated the role of cdc2 in neurofibrillary changes in the hippocampal formation, and the entorhinal and temporal cortices. Neurons with tangle-like inclusions positive for active cdc2 were found to appear first in the Pre-alpha layer of the entorhinal cortex, and then extend to other brain regions co-incident with the progressive sequence of neurofibrillary changes. This predictable progressive pattern is not associated with amyloid. The intraneuronal accumulation of active cdc2 appeared to precede the deposition of PHF-tau phosphorylated at Ser 202/Thr 205 sites. These data are consistent with the notion that cdc2 might be involved in the abnormal hyperphosphorylation of tau and consequently aggregation of tau into PHF at an early stage and that increased cdc2 activity is not consequent to the deposition of beta-amyloid in AD brain.

Adult↗

PubMed2001

Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration.

The principal protein component of paired helical filaments (PHFs) in Alzheimer disease is abnormally hyperphosphorylated tau (PHF-tau). The stress activated protein kinases JNK and p38 have been shown to phosphorylate tau at some sites only seen in PHF-tau. If JNK and p38 are involved in the abnormal hyperphosphorylation of tau, they should be activated in neurons undergoing neurofibrillary degeneration. In the present study, we determined the intracellular and regional distribution of the active forms of JNK and p38 kinase in entorhinal, hippocampal, and temporal cortices of brains staged for neurofibrillary changes according to Braak and Braak. Neurons with tangle-like inclusions positive for active forms of JNK and p38 kinase were found to appear first in the Pre-alpha layer of the entorhinal cortex, and then extend into other brain regions co-incident with the progressive sequence of neurofibrillary changes. The intraneuronal accumulation of active forms of JNK and p38 kinase apeared to precede the deposition of amyloid in the extracellular space. These data indicate that increased activation of the stress related kinases JNK and p38 occurs very early in the disease and might be involved in the intraneuronal protein phosphorylation/dephosphorylation imbalance that leads to neurofibrillary degeneration in Alzheimer disease.

Journal Article↗

PubMedDate not supplied

Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion.

Abnormally hyperphosphorylated tau which is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles is the pivotal lesion in Alzheimer disease (AD) and related tauopathies. The cosegregation of tau mutations with disease in inherited cases of frontotemporal dementia has confirmed that abnormalities in this protein can be a primary cause of neurodegeneration. Unlike normal tau that promotes assembly and maintains the structure of microtubules, the abnormally hyperphosphorylated protein sequesters normal tau, MAP1 and MAP2 and consequently disassembles microtubules. The abnormal hyperphosphorylation also promotes the self assembly of tau into tangles of PHF. The hyperphosphorylation of tau in AD is probably due to a protein phosphorylation/dephosphorylation imbalance produced by a decrease in the activity of protein phosphatase (PP)-2A and increase in the activities of tau kinases which are directly or indirectly regulated by PP-2A. Two of the most promising pharmacologic therapeutic approaches to AD are (1) the development of drugs that can inhibit the sequestration of normal MAPs by the abnormally hyperphosphorylated tau, and (2) the development of drugs that can reverse the abnormal hyperphosphorylation of tau by correcting the protein phosphorylation/dephosphorylation imbalance.

Alzheimer Disease↗