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PubMed1996

Plaque formation in brain transplants exposed to human beta-amyloid precursor protein 695.

Abnormal processing of beta-amyloid precursor protein (APP) and precipitation of amyloidogenic beta A4 peptide have been implicated in the pathogenesis of Alzheimer's disease (AD). In an attempt to generate an in vivo model of APP-associated pathology, we have introduced recombinant retroviral vectors harboring normal and mutant cDNAs for human neuron-specific APP 695 into fetal rat brain transplants. A minor population of recombinant neural cells with expression of APP was identified immunohistochemically in the grafts. The expression was maintained during an observation period of 9 months. Neurons with strong immunoreactivity for human APP exhibited markedly swollen perikarya and showed signs of cell degeneration. At 6 months post-transplantation, recombinant grafts developed APP-positive neuropil deposits with morphological features of neuritic plaques, but without beta A4 peptide immunoreactivity. No difference was observed between wild-type APP and the mutant APP construct derived from a family with autosomal dominant AD. These observations indicate that long-term neuronal overexpression of human APP has the potential to generate APP plaques in the rodent brain.

Amyloid beta-Protein Precursor↗
PubMed1999

Amyloid precursor proteins in the cerebellar cortex of Alzheimer's disease patients devoid of cerebellar beta-amyloid deposits: immunocytochemical study of five cases.

Five human brains affected by Alzheimer's disease (AD), but without cerebellar amyloid (A beta) deposits, were investigated for the presence and location of amyloid precursor proteins (APP). This was parallel to 6 AD brains with A beta deposits, 6 young controls and 6 age-matched controls. Antibodies against A beta and two epitopes of APP (amino and carboxy terminals, APP(60-100) and APP(643-695), respectively) were employed. Accumulations of APP in neurons (mainly Purkinje cells) and glial cells in the upper part of the molecular layer were far greater than those in age-matched control brains and similar to those in AD brains with A beta deposits. This suggests that changes in APP production and/or metabolism occur before A beta deposition, or that these changes can occur without amyloidogenic processing. More than 60% of positive Purkinje neurons were of normal appearance; most of them showed both APP(60-100) and APP(643-695) immunoreactivity, but a small number (<21%) reacted with only a single antiserum. A small number of Golgi, Lugaro and granule cells were APP immunopositive. In all cases, stellate and basket cells were negative, as were most glial cells other than those of the molecular layer. Folia showed two different appearances, which were particularly well displayed in three cases: "strongly" immunopositive folia with high reactivity in Purkinje cells and other neurons, and "weakly" immunopositive folia with low neuronal reactivity, but with a large number of positive glial cells in the molecular layer. The results are discussed in relation to the possible existence of types or stages of the AD process and local factors, including specific and non-specific cell factors, in the induction of APP accumulation. All these 5 cases were female, but the Apo-E 4 genotype was displayed only in two cases.

Adult↗
PubMedDate not supplied

Ovariectomy of young mutant amyloid precursor protein transgenic mice leads to increased mortality.

Alzheimer disease (AD) is a neurodegenerative disease affecting a large percentage of the elderly population. Preventative therapies for AD have been limited; however, epidemiological studies have demonstrated that estrogen replacement therapy may prevent or delay the onset of AD. Therefore, we utilized female mutant amyloid precursor protein transgenic mice (APP(SWE)), as a mouse model of AD-like pathology, to study the long-term effects of estrogen withdrawal. Interestingly, by 8 months of age 58% of the ovariectomized APP(SWE) mice had died, whereas there was no mortality in the sham ovariectomized APP(SWE) mice. This mortality was correlated with estrogen loss only in the APP(SEW) mice since background strain matched ovariectomized wild-type mice had virtually no mortality. Cerebral A beta levels in the surviving APP(SWE) ovariectomized females were increased by 50% compared to the sham ovariectomized APP(SWE) females. However, the levels of A beta in the ovariectomized APP(SWE) mice were still well below those observed in 2-year-old APP(SWE) mice that had A beta plaques. Therefore, the mildly increased A beta levels were not the suspected cause of death in these ovariectomized mice. Previous studies have demonstrated increased mortality in mice overexpressing mutant or wildtype APP independent of A beta accumulation; thus, estrogen withdrawal may potentiate this phenotype associated with APP overexpression.

Alzheimer Disease↗
PubMed1996

Effect of alkalizing agents on the processing of the beta-amyloid precursor protein.

We investigated the processing pathway of the amyloid precursor protein (APP) to the secretion of beta A4 under the treatment of ammonium chloride (NH4Cl), bafilomycin A1 (bafA1), or chloroquine, all three agents thought to raise the pH in acidic compartments. HEK-293 cells expressing wild-type APP (APPwt) and APP carrying the Swedish double mutation (APPswe) were affected in a different manner: while cells expressing APPswe decreased the secretion of beta A4 after treatment with bafA1 and NH4Cl, cells expressing APPwt compensated the drug-induced decrease in beta A4 by an increased generation of alternative beta A4-related peptides. Within cells APP accumulated, while the formation of a C-terminal fragment of APP generated by beta-secretase was completely inhibited. Thus, BafA1 and NH4Cl reduced the secretion of beta A4 by inhibiting beta-secretase. Treatment with chloroquine did not alter beta A4 secretion but, strikingly, resulted in an accumulation of intracellular beta A4. The effect of reduced APP endocytosis was studied by expressing APP molecules lacking the cytoplasmic domain (APPwt.delta. APPswe.delta). Truncation of APP reduced beta A4 secretion from APPwt but not from APPswe. BafA1 and NH4Cl treatment inhibited the formation of beta A4 in cells expressing APPswe.delta but not APPwt.delta. With these constructs, chloroquine had no effect and no accumulation of intracellular beta A4 was observed. Since alkalizing agents still affected endocytosis-deficient APP containing the Swedish double mutation, we suggest that the formation of beta A4 from this mutated APP takes place mainly in an acidic compartment along the constitutive secretory pathway. Much in contrast to this, beta A4 generation from APPwt appears to occur also in the endosomal/lysosomal compartment.

Alkalies↗
PubMed1996

Baculovirus-infected cells do not produce the amyloid peptide of Alzheimer's disease from its precursor.

The amyloid peptide (Abeta) of Alzheimer's disease (AD) is produced by proteolytic cleavage of a larger precursor, the amyloid peptide precursor or APP. The discovery of pathogenic mutations in the APP gene provides strong evidence for the hypothesis that APP metabolism is involved in the etiology of AD. To study the metabolism of the protein, human APP has been expressed in several mammalian cell types. Insect cells, infected by a recombinant baculovirus carrying the human APP sequence, also provide an interesting expression system because these cells do not produce endogenous APP. Baculovirus-infected cells synthesize very high amounts of extracellular soluble APP, after cleavage of the transmembrane protein, as described for mammalian cells. However, we demonstrate here that insect cells do not produce Abeta from APP. These results suggest that while the enzymatic activity needed for the production of soluble APP is conserved between insect and mammalian cells, the enzymes required for the production of Abeta from APP are only expressed in mammalian cells.

Alzheimer Disease↗
PubMedDate not supplied

Mutant and native human beta-amyloid precursor proteins in transgenic mouse brain.

Human beta-amyloid precursor protein (beta APP) has been targeted to transgenic neurons using synapsin I promoter-based chimeric transgenes. Native human beta APP was introduced as well as beta APP containing mutations genetically linked to familial Alzheimer's disease (AD) and to hereditary cerebral hemorrhage with amyloidosis-Dutch type. In mouse brain, human beta APP RNA was up to 60% as abundant as total endogenous beta APP RNA. Human beta APP gene expression was most abundant in the CA subfields of the hippocampus and in the piriform cortex. Correct processing of human beta APP at the beta-secretase cleavage site was demonstrated in transgenic mouse brains. Despite a 40% increase in total beta APP immunoreactivity in lines expressing mutant human beta APP, no evidence of amyloid deposition was found in brains of mice up to 14 months in age. Higher levels of mutant human beta APP, increased age, or other factors may be necessary to elicit beta-amyloid-related neuropathologies in the rodent brain.

Amyloid beta-Protein Precursor↗
PubMed1994

Detection of Actinobacillus pleuropneumoniae serotype 2 antibodies in pig sera by an inhibition enzyme immuno assay (EIA).

An inhibition Enzyme Immuno Assay (EIA) for detection of antibodies against A. pleuropneumoniae serotype 2 (App-2) in pig sera, based on the inhibition of the binding of an App-2 specific monoclonal antibody was established. The monoclonal antibody (mAb 102-G02) was found to be directed against an epitope on the O-chain of App-2 LPS. Some App-2 isolates did not react with the mAb 102-G02. These isolates are referred to as App-2X. In the inhibition EIA highly purified App-2 LPS ws used to coat microtiter plates. Serial dilutions of pig sera were added to the plates prior to the mAb 102-G02. The degree of binding of App-2 antibodies from pig sera was determined as the percentage inhibition of the mAb 102-G02. Pig sera from specific pathogen free (SPF) herds, from experimentally infected animals, and from conventionel herds were tested. A serum dilution of 1/200 was found to be optimal, when using 50% inhibition as the discriminating inhibition percentage. Serum from App-2X infected herds showed a lower reactivity as compared to serum from App-2 infected herds. No crossreactivity was observed with serum from pigs infected with other App serotypes. The sensitivity and specificity were 100% and 98.9%, respectively.

Actinobacillus Infections↗
PubMed2005

Mu-calpain is functionally required for alpha-processing of Alzheimer's beta-amyloid precursor protein.

Alzheimer's beta-amyloid precursor protein (APP) is normally processed by an unidentified alpha-secretase. A unique feature of this protease is its high sensitivity to phorbol esters, yet the mechanism involved is unclear. We have previously reported that phorbol 12,13-dibutyrate (PDBu) activates calpain, a Ca2+-dependent protease, and PDBu-induced release of APPs (secreted APP) is sensitive to calpain inhibitors, suggesting that calpain is involved in APP alpha-processing. In the present study, we found that PDBu markedly promoted the expression of both mu- and m-calpains in cultured fibroblasts. Dose-response and time course studies revealed that mu-calpain was more sensitive to PDBu than m-calpain and the temporal course of the mu-calpain change coincides better with that of APPs release. Moreover, the stimulatory effect of PDBu on mu-calpain was selectively blocked by mu-calpain-specific siRNA (small interference RNA) and the blockage was accompanied by a concomitant decrease in APPs release. In contrast, m-calpain siRNA did not affect APPs release significantly. Measurement of amyloid beta protein (Abeta) release in the mu-calpain siRNA-treated cells indicated that Abeta40 and Abeta42 levels inversely changed in relation to APPs, and the changes in Abeta42 were more prominent than in Abeta40. Together, these data suggest that calpain, particularly mu-calpain, is a potential candidate for alpha-secretase in the regulated APP alpha-processing, and that changes in this protease can affect the outcome of the overall APP processing.

Alzheimer Disease↗
PubMed2006

The amyloid precursor protein and postnatal neurogenesis/neuroregeneration.

The amyloid precursor protein (APP) is the source of amyloid-beta (Abeta) peptide, produced via its sequential cleavage beta- and gamma-secretases. Various biophysical forms of Abeta (and the mutations of APP which results in their elevated levels) have been implicated in the etiology and early onset of Alzheimer's disease. APP's evolutionary conservation and the existence of APP-like isoforms (APLP1 and APLP2) which lack the Abeta sequence, however, suggest that these might have important physiological functions that are unrelated to Abeta production. Soluble N-terminal fragments of APP have been known to be neuroprotective, and the interaction of its cytoplasmic C-terminus with a myriad of proteins associates it with diverse processes such as axonal transport and transcriptional regulation. The notion for an essential postnatal function of APP has been demonstrated genetically, as mice deficient in both APP and APLP2 or all three APP isoforms exhibit early postnatal lethality and neuroanatomical abnormalities. Recent findings have also brought to light two possible functions of the APP family in the brain-regulation of neural progenitor cell proliferation and axonal outgrowth after injury. Interestingly, these two apparently related neurogenic/neuroregenerative functions of APP involve two separate domains of the molecule.

Amyloid beta-Protein Precursor↗
PubMed2004

Amyloid precursor protein mRNA levels in Alzheimer's disease brain.

Insoluble beta-amyloid deposits in Alzheimer's disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls (p=0.002). There was no change in the mRNA levels of KPI-(APP 695) (p=0.898). Therefore, whilst KPI-mRNA levels remained stable the KPI(+) species increased specifically in the AD brains.

Adult↗
PubMed2004

Novel alpha-secretase cleavage of Alzheimer's amyloid beta precursor protein in the endoplasmic reticulum of COS7 cells.

In the processing of APP, alpha- and beta-secretase pathways compete with each other for cleaving APP. Therefore, physiologically these two secretases are likely to colocalize in the same subcellular compartments. Previously beta-secretase cleavage of APP was found in the endoplasmic reticulum (ER). We herein tested whether alpha-secretase cleavage is also detected in the ER. We used experimental system of COS7 cells transfected with cDNA encoding human APP695, and the cell lysates and media were examined for its proteolytic products. When APP expression is concentrated in the ER by BFA-mediated transport inhibition or by using mutant APP harboring an ER-retrieval motif, alpha-secretase product sAPPalpha was accumulated in the cells. Immunofluorescence microscopy revealed that the ER-targeted APP produced intracellular accumulation of sAPPalpha, colocalizing with an ER marker. These results indicate that alpha-secretase cleavage of APP occurs in the ER. Further we examined the effects of phorbol ester PDBu, a direct activator of PKC, on the alpha-secretase and beta-secretase cleavages of APP occurring in the ER. Treatment with PDBu of COS7 cells transfected with the ER-targeted APP increased production of sAPPalpha and conversely decreased production of beta-secretase product sAPPbeta. Thus, in the ER, alpha-secretase competes with beta-secretase for cleaving APP and such competitive correlation might modulate the production of Abeta42 found in this compartment.

Amyloid Precursor Protein Secretases↗
PubMed2006

Decoy mRNAs reduce beta-amyloid precursor protein mRNA in neuronal cells.

Overproduction of amyloid precursor protein (APP) and beta-amyloid likely contribute to neurodegeneration in Alzheimer's disease (AD). In an effort to understand neuronal APP gene regulation, we identified a 52 base element (52sce) immediately downstream from the stop codon that stabilizes APP mRNA. Deletion of this domain drastically destabilized APP mRNAs and reduced APP synthesis in vitro. Chimeric globin-APP mRNAs containing the globin coding sequence fused to the entire APP 3'-UTR, showed regulation similar to full-length APP mRNA. A variety of cytoplasmic lysates contain 52sce RNA binding activity, suggesting cis-trans interactions regulate the element's functionality. Finally, the overexpression of chimeric mRNAs, containing the GFP coding sequence and APP 3'-UTR, dramatically reduced endogenous APP steady-state levels in SH-SY5Y neuroblastoma cells and suggests a novel approach to reduce the amyloid burden in AD patients.

3' Untranslated Regions↗
PubMed2002

Transcriptional activation and increase in expression of Alzheimer's beta-amyloid precursor protein gene is mediated by TGF-beta in normal human astrocytes.

The overexpression of the Alzheimer amyloid precursor protein (APP) and its subsequent proteolytic processing may be one of several factors contributing to amyloid beta-peptide (Abeta) deposition in plaques and microvasculature in Alzheimer's disease (AD) brain. Cytokines and growth factors can influence the expression of APP in response to brain injury, but the underlying mechanisms are largely unknown. We examined the mechanisms by which transforming growth factor-beta (TGF-beta) affects the expression of APP in normal human astrocytes. We report that, TGF-beta up-regulated the expression of APP at the transcription level as determined by nuclear run-on experiments. Transient transfection of astrocytes with APP gene promoter (-2832 bp) chloramphenicol acetyltransferase (CAT) reporter constructs led to increased reporter activity upon TGF-beta stimulation. This reporter activity was mainly attributed to the APP proximal domain (-488 bp). The increase in APP gene transcription was associated with significant accumulation of intracellular APP, APP carboxyl terminal derived fragments, and total secreted Abeta. In addition, we observed a significant increase in levels of TGF-beta in Abeta plaques and its immediate vicinity in AD-affected brain relative to controls. These results indicate that high levels of TGF-beta in the cortex, may serve to up-regulate APP synthesis in reactive astrocytes and indirectly contributes to Abeta deposition. Closely related processes may induce cerebrovascular pathology in AD brain.

Alzheimer Disease↗
PubMed2002

Transforming growth factor-beta-induced transcription of the Alzheimer beta-amyloid precursor protein gene involves interaction between the CTCF-complex and Smads.

Transforming growth factor-beta-1 (TGF-beta), a key regulator of the brain responses to injury and inflammation, has been implicated in upregulating the expression of the Alzheimer amyloid precursor protein (APP) and Alzheimer's disease (AD) pathogenesis. However, little is known about the mechanisms underlying the effects of TGF-beta on APP expression. Analysis of APP promoter activity upstream of the chloramphenicol acetyltransferase reporter gene in normal human astrocytes (NHAs), revealed that the APP promoter binding beta (APBbeta) site (-93/-82) is responsive to TGF-beta. This site interacts with the zinc finger nuclear factor CTCF, involved in APP transcriptional activity. As determined by gel shift assay, there was no significant difference in the CTCF-APBbeta complex binding activity in the presence or absence of TGF-beta treatment of NHAs. To further investigate the contributions of the CTCF-complex and Smad proteins to the TGF-beta induced APP promoter activity, we examined the distribution of these factors and their DNA binding activity. Interestingly, upon TGF-beta treatment both Smads 3 and 4 were translocated to the nuclei in contrast to Smad 2, which was cytoplasmic. However, CTCF was predominantly localized in the nuclei irrespective of TGF-beta treatment. Gel super shift assay coupled with Western blot analysis showed that Smads 3 and 4 specifically associated with the CTCF-APBbeta complex. In addition, AD brain sections showed increased expression and nuclear localization of Smad 4, which correlated with higher levels of APP and TGF-beta. However, over expression of Smad 4 on its own was not sufficient to affect APP expression. These results demonstrate that TGF-beta activation of Smad protein complexes promotes transcription of the APP gene. Increased synthesis of APP may in part determine Abeta production and deposition in affected AD brain.

Astrocytes↗
PubMed2002

Amyloid precursor protein gene disruption attenuates degeneration of substantia nigra compacta neurons following axotomy.

Our past work has shown that the C-terminal fragment of amyloid precursor protein (APP) translocated to the nucleus in neurons destined for delayed excitotoxic degeneration. To test whether nuclear APP fragments also play a role in the progressive loss of dopaminergic (DA) substantia nigra compacta (SNc) neurons, we performed unilateral medial forebrain bundle (MFB) transection on APP wild type (WT) and on mice with disruption of the APP gene (KO). In WT mice immunoreactivity for APP C-terminal, beta-amyloid and Alz90 epitopes appeared in the nuclei of axotomized DA neurons at 3 days post-lesion (dpl), persisted at 7 dpl and was absent in 14 dpl mice. APP N-terminal immunoreactivity was restricted to the cytosol at all time points, precluding the possibility of full length APP in the nucleus. Nuclear localization of APP epitopes was absent in neurons of the contralateral SNc or in neurons of the ipsilateral ventral tegmental area and SN reticulata. The presence of APP C-terminal and Alz90 domains was confirmed by Western blotting performed on the nuclear fraction of the SN ipsilateral to the axotomy. Quantitative morphometric analysis revealed that WT mice demonstrated earlier and more profound loss of tyrosine hydroxylase+SNc neurons than did KO mice. These data showed that a novel nuclear C-terminal fragment appeared coincident with SNc neuron degeneration, and that APP deficiency correlated with significant neuroprotection in vivo.

Amyloid beta-Protein Precursor↗
PubMed2003

Regulation of amyloid precursor protein expression and secretion via activation of ERK1/2 by hepatocyte growth factor in HEK293 cells transfected with APP751.

The increased intracellular levels and aberrant processing of the amyloid precursor protein (APP) are associated with beta-amyloid peptide (A beta) production, cerebrovascular amyloid deposition, and amyloid plaque formation. Here we report that APP level, soluble APP (sAPP) secretion, and A beta production in HEK293 cells transfected with either wild-type APP(751) or APP(751) carrying the Swedish mutation are all elevated by hepatocyte growth factor (HGF). We investigated the potential molecular mechanisms underlying the HGF effect. Our data show that HGF stimulated extended activation of extracellular signal-regulated protein kinases (ERK1/2). Pretreatment of cells with inhibitors (UO126 or PD98059) for MEK, the upstream kinase of ERK1/2, abolished ERK1/2 activation evoked by HGF, and abrogated HGF-induced increases in APP levels and sAPP secretion. In addition, transient expression of active MEK1 activated ERK1/2 and increased intracellular APP levels and sAPP secretion. Inhibition of ERK1/2 activity, however, failed to block HGF-stimulated A beta production. Consistently, transient expression of active MEK1 did not increase A beta accumulation. Taken together, these results suggest that: (1) HGF regulates the intracellular levels of APP and the secretion of sAPP and A beta; (2) the modulation of APP levels and sAPP secretion induced by HGF is mediated via the MEK1/ERK1/2 signaling pathway; (3) HGF-stimulated A beta production is independent of ERK activity and, therefore, independent of HGF-evoked elevation of intracellular APP levels.

Amyloid beta-Protein Precursor↗
PubMed1997

Characterization of beta-amyloid peptide precursor processing by the yeast Yap3 and Mkc7 proteases.

Two proteases, denoted beta- and gamma-secretase, process the beta-amyloid peptide precursor (APP) to yield the Abeta peptides involved in Alzheimer's disease. A third protein, alpha-secretase, cleaves APP near the middle of the Abeta sequence and thus prevents Abeta formation. These enzymes have defied identification. Because of its similarity to the systems of mammalian cells the yeast secretory system has provided important clues for finding mammalian processing enzymes. When expressed in Saccharomyces cerevisiae APP is processed by enzymes that possess the specificity of the alpha-secretases of multicellular organisms. APP processing by alpha-secretases occurred in sec1 and sec7 mutants, in which transport to the cell surface or to the vacuole is blocked, but not in sec17 or sec18 mutants, in which transport from the endoplasmic reticulum to the Golgi is blocked. Neutralization of the vacuole by NH4Cl did not block alpha-secretase action. The time course of processing of a pro-alpha-factor leader-APP chimera showed that processing by Kex2 protease, a Golgi protease that removes the leader, preceded processing by alpha-secretase. Deletions of the genes encoding the GPI-linked aspartyl proteases Yap3 and Mkc7 decreased alpha-secretase activity by 56 and 29%, respectively; whereas, the double deletion decreased the activity by 86%. An altered form of APP-695, in which glutamine replaced Lys-612 at the cleavage site, is cleaved by Yap3 at 5% the rate of the wild-type APP. Mkc7 protease cleaved APP (K612Q) at about 20% the rate of wild-type APP. The simplest interpretation of these results is that Yap3 and Mkc7 proteases are alpha-secretases which act on APP in the late Golgi. They suggest that GPI-linked aspartyl proteases should be investigated as candidate secretases in mammalian tissues.

Alzheimer Disease↗
PubMed2002

Anti-apoptotic wild-type Alzheimer amyloid precursor protein signaling involves the p38 mitogen-activated protein kinase/MEF2 pathway.

Alzheimer amyloid precursor protein (APP) effectively protects against apoptosis in neuronal cells under stress, but the mechanisms of this anti-apoptotic effect remain largely unknown. Transcription factors act as critical molecular switches in promoting neuronal survival. The myocyte enhancer factor-2 (MEF2) is a transcription factor, and is known to be necessary for neurogenesis and activity-dependent neuronal survival. This study examined the possible role of MEF2 in the anti-apoptotic signaling pathways activated by APP. We report that expression of wild-type human APP (hAPPwt) but not familial Alzheimer's disease mutant APP (FAD-hAPPmut) in APP-deficient rat B103 cells led to a significant increase in the level of phosphorylated MEF2. This differential phosphorylation was dependent on enhanced activation of p38 mitogen-activated protein kinase (p38 MAPK). Also, expression of hAPPwt mediated an increase in MEF2 DNA binding affinity that correlated with p38 MAPK-dependent trans-activation of a MEF2-responsive reporter gene. Furthermore, over-expression of dominant negative MEF2 in hAPPwt-expressing cells enhanced staurosporine-induced apoptosis, in contrast MEF2wt enhanced the capacity of hAPPwt to confer resistance to apoptosis. Thus, MEF2 plays a critical role in APP-mediated signaling pathways that inhibit neuronal apoptosis. A model of anti-apoptotic APP signaling is proposed where APP mediates p38 MAPK-dependent phosphorylation and activation of MEF2. Once activated MEF2 regulates neuronal survival by stimulation of MEF2-dependent gene transcriptions. Alteration of this function by mutations in APP and aberrant APP processing could contribute to neuronal degeneration seen in AD.

Alzheimer Disease↗