Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer's disease pathology progression.

A recent large genome-wide association study has identified EGFR (encoding the epidermal growth factor EGFR) as a new genetic risk factor for late-onset AD. SHIP2, encoded by INPPL1, is taking part in the signalling and interactome of several growth factor receptors, such as the EGFR. While INPPL1 has been identified as one of the most significant genes whose RNA expression correlates with cognitive decline, the potential alteration of SHIP2 expression and localization during the progression of AD remains largely unknown. Here we report that gene expression of both EGFR and INPPL1 was upregulated in AD brains. SHIP2 immunoreactivity was predominantly detected in plaque-associated astrocytes and dystrophic neurites and its increase was correlated with amyloid load in the brain of human AD and of 5xFAD transgenic mouse model of AD. While mRNA of INPPL1 was increased in AD, SHIP2 protein undergoes a significant solubility change being depleted from the soluble fraction of AD brain homogenates and co-enriched with EGFR in the insoluble fraction. Using FRET-based flow cytometry biosensor assay for tau-tau interaction, overexpression of SHIP2 significantly increased the FRET signal while siRNA-mediated downexpression of SHIP2 significantly decreased FRET signal. Genetic association analyses suggest that some variants in INPPL1 locus are associated with the level of CSF pTau. Our data support the hypothesis that SHIP2 is an intermediate key player of EGFR and AD pathology linking amyloid and tau pathologies in human AD.

Picalm reduction exacerbates tau pathology in a murine tauopathy model.

Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer's disease (AD) after APOE and BIN1. PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubule-associated protein tau (MAPT) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau-MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPicalm+/- by crossing Tg30 tau transgenic mice with Picalm-haploinsufficient mice to test whether Picalm reduction may modulate tau pathology. While Picalm haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPicalm+/- mice developed markedly more severe motor deficits than Tg30 by the age of 9 months. Tg30xPicalm+/- had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that Picalm haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and tau-mediated neurodegeneration, supporting a role for changes in Picalm expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.

Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model.

Impaired adult hippocampal neurogenesis has been reported as a feature of Alzheimer's disease and other tauopathies and might contribute to defects in learning and memory in these diseases. To assess the interference of tau pathology, a common key-lesion in these diseases, with adult hippocampal neurogenesis we analyzed adult neurogenesis in the hippocampal dentate gyrus in wild-type mice, Tg30 mice expressing a FTDP-17 mutant tau and the same Tg30 mice deficient for mouse tau (Tg30/tauKO). The volume of the granular layer, the number of granule cells and of neuronal precursors expressing the immature markers DCX or 3R-tau were analyzed in the dentate gyrus (DG) using unbiased stereological methods. The co-localization of neurogenic markers with the human mutant tau was also analyzed. We observed a significant reduction of the volume of the granular layer and of granule cells number in mutant tau Tg30 mice, but not in Tg30/tauKO mice. The number of neuronal precursors expressing the immature markers DCX or 3R-tau (the latter only expressed in wild-type and Tg30 mice) and the number of cells expressing the proliferation marker Ki-67 in the neurogenic subgranular zone of the DG was reduced in Tg30 but not in Tg30/tauKO mice. The density of phosphotau positive cells in the DG and the level of soluble human phosphotau was lower in Tg30/tauKO compared to Tg30 mice. The human mutant tau was expressed in mature granule cells in Tg30 and Tg30/tauKO mice but was not expressed in Sox2 positive neural stem cells and in DCX positive neuronal precursors/immature newborn neurons. These results demonstrate an impairment of adult hippocampal neurogenesis in a FTDP-17 mutant tau mice resulting from a decrease of proliferation affecting the pool of neuronal precursors. The mutant tau was not expressed in precursors cells in these mutant tau mice, suggesting that this neurogenic defect is cell non-autonomous. Interestingly, expression of endogenous wild-type tau in mature granule cells was necessary to observe this toxic effect of human mutant tau, since this impaired adult neurogenesis was rescued by lowering tau expression in Tg30/tauKO mice. These observations suggest that development of tau pathology in granule cells of the dentate gyrus is responsible for reduction of adult hippocampal neurogenesis also in human tauopathies by impairing proliferation of neuronal precursors, and that reduction of tau expression might be an approach to rescue this impairment.

Amyloid-ß pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo.

Neuropathological analysis in Alzheimer's disease (AD) and experimental evidence in transgenic models overexpressing frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutant tau suggest that amyloid-ß pathology enhances the development of tau pathology. In this work, we analyzed this interaction independently of the overexpression of an FTDP-17 mutant tau, by analyzing tau pathology in wild-type (WT), 5xFAD, APP-/- and tau-/- mice after stereotaxic injection in the somatosensory cortex of short-length native human AD-PHF. Gallyas and phosphotau-positive tau inclusions developed in WT, 5xFAD, and APP-/- but not in tau-/- mice. Ultrastructural analysis demonstrated their intracellular localization and that they were composed of straight filaments. These seeded tau inclusions were composed only of endogenous murine tau exhibiting a tau antigenic profile similar to tau aggregates in AD. Insoluble tau level was higher and ipsilateral anteroposterior and contralateral cortical spreading of tau inclusions was more important in AD-PHF-injected 5xFAD mice than in WT mice. The formation of large plaque-associated dystrophic neurites positive for oligomeric and phosphotau was observed in 5xFAD mice injected with AD-PHF but never in control-injected or in non-injected 5xFAD mice. An increased level of the p25 activator of CDK5 kinase was found in AD-PHF-injected 5xFAD mice. These data demonstrate in vivo that the presence of Aß pathology enhances experimentally induced tau seeding of endogenous, wild-type tau expressed at physiological level, and demonstrate the fibrillar nature of heterotopically seeded endogenous tau. These observations further support the hypothesis that Aß enhances tau pathology development in AD through increased pathological tau spreading.

High-Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo.

In Alzheimer disease, the development of tau pathology follows neuroanatomically connected pathways, suggesting that abnormal tau species might recruit normal tau by passage from cell to cell. Herein, we analyzed the effect of stereotaxic brain injection of human Alzheimer high-molecular-weight paired helical filaments (PHFs) in the dentate gyrus of wild-type and mutant tau THY-Tau22 mice. After 3 months of incubation, wild-type and THY-Tau22 mice developed an atrophy of the dentate gyrus and a tau pathology characterized by Gallyas and tau-positive grain-like inclusions into granule cells that extended in the hippocampal hilus and eventually away into the alveus, and the fimbria. Gallyas-positive neuropil threads and oligodendroglial coiled bodies were also observed. These tau inclusions were composed only of mouse tau, and were immunoreactive with antibodies to 4R tau, phosphotau, misfolded tau, ubiquitin, and p62. Although local hyperphosphorylation of tau was increased in the dentate gyrus in THY-Tau22 mice, the development of neurofibrillary tangles made of mutant human tau was not accelerated in the hippocampus, indicating that wild-type human PHFs were inefficient in seeding tau aggregates made of G272V/P301S mutant human tau. Our results indicate thus that injection of human wild-type Alzheimer PHF seeded aggregation of wild-type murine tau into an argyrophilic 4R tau pathology, and constitutes an interesting model independent of expression of a mutant tau protein.

Motor deficit in a tauopathy model is induced by disturbances of axonal transport leading to dying-back degeneration and denervation of neuromuscular junctions.

Several neurodegenerative diseases are characterized by both cognitive and motor deficits associated with accumulation of tau aggregates in brain, brainstem, and spinal cord. The Tg30 murine tauopathy model expresses a human tau protein bearing two frontotemporal dementia with Parkinsonism linked to chromosome 17 pathogenic mutations and develops a severe motor deficit and tau aggregates in brain and spinal cord. To investigate the origin of this motor deficit, we analyzed the age-dependent innervation status of the neuromuscular junctions and mutant tau expression in Tg30 mice. The human transgenic tau was detected from postnatal day 7 onward in motoneurons, axons in the sciatic nerve, and axon terminals of the neuromuscular junctions. The development and maturation of neuromuscular junctions were not disrupted in Tg30 mice, but their maintenance was disturbed in adult Tg30 mice, resulting in a progressive and severe muscle denervation. This muscle denervation was associated with early electrophysiological signs of muscle spontaneous activities and histological signs of muscle degeneration. Early loss of synaptic vesicles in axon terminals preceding motor deficits, accumulation of Gallyas-positive aggregates, and cathepsin-positive vesicular clusters in axons in the sciatic nerve suggest that this denervation results from disturbances of axonal transport. This physiopathological mechanism might be responsible for motor signs observed in some human tauopathies, and for synaptic dysfunction resulting from alterations at the presynaptic level in these diseases.

Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology.

ITPKB phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate and controls signal transduction in various hematopoietic cells. Surprisingly, it has been reported that the ITPKB messenger RNA level is significantly increased in the cerebral cortex of patients with Alzheimer's disease, compared with control subjects. As extracellular signal-regulated kinases 1/2 activation is increased in the Alzheimer brain and as ITPKB is a regulator of extracellular signal-regulated kinases 1/2 activation in some hematopoietic cells, we tested whether this increased activation in Alzheimer's disease might be related to an increased activity of ITPKB. We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased ß-secretase 1 activity leading to overproduction of amyloid-ß peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-ß peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and ß-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-ß40 peptide production and tau hyperphosphorylation. No impact on pathology was observed in the 5X familial Alzheimer's disease mouse model when a catalytically inactive ITPKB protein was overexpressed. Together, our results point to the ITPKB/inositol 1,3,4,5-tetrakisphosphate/extracellular signal-regulated kinases 1/2 signalling pathway as an important regulator of neuronal cell apoptosis, APP processing and tau phosphorylation in Alzheimer's disease, and suggest that ITPKB could represent a new target for reducing pathology in human patients with Alzheimer's disease with ITPKB expression.

Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice.

Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an Aß pathology. The mechanisms leading to this enhanced tau pathology are not well understood. We have performed a detailed analysis of tau misprocessing in a new transgenic mouse model combining APP, PS1 and tau mutations (5xFAD×Tg30 mice) by comparison with littermates expressing only a FTD mutant tau (Tg30 mice). These 5xFAD×Tg30 mice showed a more severe deficient motor phenotype than Tg30 mice and developed with age a dramatically accelerated NFT load in the brain compared to Tg30 mice. Insoluble tau in 5xFAD×Tg30 mice compared to insoluble tau in Tg30 mice showed increased phosphorylation, enhanced misfolding and truncation changes mimicking more closely the post-translational changes characteristic of PHF-tau in Alzheimer's disease. Endogenous wild-type mouse tau was recruited at much higher levels in insoluble tau in 5xFAD×Tg30 than in Tg30 mice. Extracellular amyloid load, Aß40 and Aß42, ß-CTFs and ß-CTF phosphorylation levels were lower in 5xFAD×Tg30 mice than in 5xFAD mice. Despite this reduction of Aß, a significant hippocampal neuronal loss was observed in 5xFAD×Tg30 but not in 5xFAD mice indicating its closer association with increased tau pathology. This 5xFAD×Tg30 model thus mimics more faithfully tau pathology and neuronal loss observed in AD and suggests that additional post-translational changes in tau and self-recruitment of endogenous tau drive the enhanced tau pathology developing in the presence of Aß pathology.

Downregulation of hsa-miR-132 and hsa-miR-129: non-coding RNA molecular signatures of Alzheimer's disease.

Alzheimer's disease (AD) affects the elderly population by causing memory impairments, cognitive and behavioral abnormalities. Currently, no curative treatments exist, emphasizing the need to explore therapeutic options that modify the progression of the disease. MicroRNAs (miRNAs), as non-coding RNAs, demonstrate multifaceted targeting potential and are known to be dysregulated in AD pathology. This mini review focuses on two promising miRNAs, hsa-miR-132 and hsa-miR-129, which consistently exhibit differential regulation in AD. By employing computational predictions and referencing published RNA sequencing dataset, we elucidate the intricate miRNA-mRNA target relationships associated with hsa-miR-132 and hsa-miR-129. Our review consistently identifies the downregulation of hsa-miR-132 and hsa-miR-129 in AD brains as a non-coding RNA molecular signature across studies conducted over the past 15 years in AD research.

Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice.

Lack of tau expression has been reported to protect against excitotoxicity and to prevent memory deficits in mice expressing mutant amyloid precursor protein (APP) identified in familial Alzheimer disease. In APP mice, mutant presenilin 1 (PS1) enhances generation of Aß42 and inhibits cell survival pathways. It is unknown whether the deficient phenotype induced by concomitant expression of mutant PS1 is rescued by absence of tau. In this study, we have analyzed the effect of tau deletion in mice expressing mutant APP and PS1. Although APP/PS1/tau(+/+) mice had a reduced survival, developed spatial memory deficits at 6 months and motor impairments at 12 months, these deficits were rescued in APP/PS1/tau(-/-) mice. Neuronal loss and synaptic loss in APP/PS1/tau(+/+) mice were rescued in the APP/PS1/tau(-/-) mice. The amyloid plaque burden was decreased by roughly 50% in the cortex and the spinal cord of the APP/PS1/tau(-/-) mice. The levels of soluble and insoluble Aß40 and Aß42, and the Aß42/Aß40 ratio were reduced in APP/PS1/tau(-/-) mice. Levels of phosphorylated APP, of ß-C-terminal fragments (CTFs), and of ß-secretase 1 (BACE1) were also reduced, suggesting that ß-secretase cleavage of APP was reduced in APP/PS1/tau(-/-) mice. Our results indicate that tau deletion had a protective effect against amyloid induced toxicity even in the presence of mutant PS1 and reduced the production of Aß.

Myopic (Peri)papillary Changes and Visual Field Defects.

Purpose: Myopic eyes combining gamma peripapillary atrophy and peripapillary staphyloma were sorted according to the presence of intrachoroidal cavitation (PICCs) or its absence (combinations). Visual field defects (VFDs) and factors discriminating these groups were analyzed. Methods: These groups were sorted by optical coherence tomography. VFDs were assessed using the Humphrey® Field Analyzer 3, SITA standard. Ovality index (OI) was the ratio between the shortest and longest diameters of the disc. The proportions of PICCs, lamina cribrosa defects (LCDs) and clusters in each Garway-Heath's sector (A-F) were analyzed. All variables were compared between PICCs and combinations. A multivariate logistic regression analysis was performed ultimately. Results: Of the 93 eyes, we obtained, 20 PICCs and 73 combinations. The prevalence of VFDs and LCDs in PICCs were 65% (13/20) and 30% (6/20), respectively. PICCs 85% (17/20) and LCDs 12% (11/93) predominated in sector B (inferotemporal) and clusters 9.7% (9/93) in the corresponding sector. The proportion of VFDs was significantly higher in PICCs than combinations (p < 0.001). In sector B, the proportion of LCDs was significantly higher in PICCs than combinations (p = 0.011). The mean OI was significantly lower (p < 0.001) in PICCs than combinations. Multivariate logistic regression analysis concluded that mean OI (p < 0.001) was the only statistically significant factor discriminating PICCs and combinations. Conclusion: Mean OI discriminating PICCs from combinations is further evidence of a gradation of structural changes between them. It could be related to the higher proportion of VFDs in PICCs. The predominant distribution of PICCs infero-temporally supports PICC as a cause of uncertainty in glaucoma diagnosis in high myopia. Furthermore, the highest proportion of PICCs and LCDs in this sector highlights its vulnerability to damage in myopic eyes and deserves further investigation as it is also primarily involved in glaucoma.

Peripapillary intrachoroidal cavitation at the crossroads of peripapillary myopic changes.

AIM: To analyze the prevalence of peripapillary intra-choroidal cavitation (PICC) in eyes with gamma peripapillary atrophy (γPPA), in eyes with peripapillary staphyloma (PPS) and in those combining γPPA and PPS and to analyze border tissue discontinuity in PICC. METHODS: This prospective cross-sectional non interventional study included highly myopic eyes. Non-highly myopic eyes were used as control. Radial and linear scans centered on the optic nerve head were performed using spectral-domain optical coherence tomography. Variables were analyzed along the twelve hourly optical coherence tomography sections in both eyes of each subject. RESULTS: A total of 667 eyes of 334 subjects were included: 229 (34.3%) highly myopic eyes and 438 (65.7%) non highly myopic eyes. The mean age of the highly myopic group was 48.99±17.81y. PICC was found in a total of 40 eyes and in 13.2% (29/220) of highly myopic eyes. PICC was found in 10.4% (40/386) of eyes with γPPA, in 20.5% (40/195) of eyes with PPS and in 22.7% (40/176) of those combining γPPA and PPS. All the eyes with PICC showed the co-existence of γPPA and PPS whereas none of the eyes presenting only one of these entities exhibited PICC. A border tissue discontinuity in the γPPA area was found in all eyes with PICC. CONCLUSION: We confirm the presence of a border tissue discontinuity in the γPPA area of all eyes with PICC. These findings suggest the involvement of mechanical factors in the pathogenesis of PICC which may contribute to PICC-related visual field defects.

Accelerated human mutant tau aggregation by knocking out murine tau in a transgenic mouse model.

Many models of human tauopathies have been generated in mice by expression of a human mutant tau with maintained expression of mouse endogenous tau. Because murine tau might interfere with the toxic effects of human mutant tau, we generated a model in which a pathogenic human tau protein is expressed in the absence of wild-type tau protein, with the aim of facilitating the study of the pathogenic role of the mutant tau and to reproduce more faithfully a human tauopathy. The Tg30 line is a tau transgenic mouse model overexpressing human 1N4R double-mutant tau (P301S and G272V) that develops Alzheimer's disease-like neurofibrillary tangles in an age-dependent manner. By crossing Tg30 mice with mice invalidated for their endogenous tau gene, we obtained Tg30xtau(-/-) mice that express only exogenous human double-mutant 1N4R tau. Although Tg30xtau(-/-) mice express less tau protein compared with Tg30, they exhibit signs of decreased survival, increased proportion of sarkosyl-insoluble tau in the brain and in the spinal cord, increased number of Gallyas-positive neurofibrillary tangles in the hippocampus, increased number of inclusions in the spinal cord, and a more severe motor phenotype. Deletion of murine tau accelerated tau aggregation during aging of this mutant tau transgenic model, suggesting that murine tau could interfere with the development of tau pathology in transgenic models of human tauopathies.

PICALM and Alzheimer's Disease: An Update and Perspectives.

Genome-wide association studies (GWAS) have identified the PICALM (Phosphatidylinositol binding clathrin-assembly protein) gene as the most significant genetic susceptibility locus after APOE and BIN1. PICALM is a clathrin-adaptor protein that plays a critical role in clathrin-mediated endocytosis and autophagy. Since the effects of genetic variants of PICALM as AD-susceptibility loci have been confirmed by independent genetic studies in several distinct cohorts, there has been a number of in vitro and in vivo studies attempting to elucidate the underlying mechanism by which PICALM modulates AD risk. While differential modulation of APP processing and Aß transcytosis by PICALM has been reported, significant effects of PICALM modulation of tau pathology progression have also been evidenced in Alzheimer's disease models. In this review, we summarize the current knowledge about PICALM, its physiological functions, genetic variants, post-translational modifications and relevance to AD pathogenesis.

Analysis of Peripapillary Intrachoroidal Cavitation and Myopic Peripapillary Distortions in Polar Regions by Optical Coherence Tomography.

Purpose: To compare the peripapillary polar characteristics in eyes combining peripapillary staphyloma and gamma peripapillary atrophy according to whether peripapillary intrachoroidal cavitation (PICC) was present or absent (combination-group). Patients and methods: This prospective non-interventional cross-sectional study included 667 eyes of 334 subjects. From the polar peripapillary regions to the opening of Bruch's membrane, the following elements and their topographic relationships were analyzed using optical coherence tomography sections: configuration of the posterior curvature of the choroid, visibility of the subarachnoid space (SAS), and suprachoroidal detachment (SCD). Chi-squared and Fisher exact tests were used for statistical analysis. Results: The protrusion of the posterior choroidal wall, with anterior elevation on either side, observed in both groups progressed and transformed into a wedge-shaped deformity on the side of gamma peripapillary atrophy. This wedge configuration was significantly more frequent in PICC-group than in combination-group (p = 0.004 and p < 0.001) for the upper and lower poles, respectively. SAS was more frequently observed in PICC-group than in combination-group (p = 0.002 and p < 0.001) for the upper and lower poles, respectively. SCD was detected exclusively in PICC-group (p < 0.001, both poles). The wedge-shaped configuration and the SCD were aligned antero-posteriorly with the SAS. Conclusion: We confirmed that PICC is an SCD. We observed its constant alignment with the SAS. We suggest that the tensile forces of the optic nerve sheaths during adduction promote the collapse of the scleral flange onto the SAS, leading to PICC. Further studies are warranted to confirm this hypothesis.

Tau Pathology and Adult Hippocampal Neurogenesis: What Tau Mouse Models Tell us?

Adult hippocampal neurogenesis (AHN) has been widely confirmed in mammalian brains. A growing body of evidence points to the fact that AHN sustains hippocampal-dependent functions such as learning and memory. Impaired AHN has been reported in post-mortem human brain hippocampus of Alzheimer's disease (AD) and is considered to contribute to defects in learning and memory. Neurofibrillary tangles (NFTs) and amyloid plaques are the two key neuropathological hallmarks of AD. NFTs are composed of abnormal tau proteins accumulating in many brain areas during the progression of the disease, including in the hippocampus. The physiological role of tau and impact of tau pathology on AHN is still poorly understood. Modifications in AHN have also been reported in some tau transgenic and tau-deleted mouse models. We present here a brief review of advances in the relationship between development of tau pathology and AHN in AD and what insights have been gained from studies in tau mouse models.

Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity.

Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in Alzheimer disease (AD) physiopathology impairs lipid synthesis needed for cortical networks' activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation were inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains. Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP-silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by a PPARα-specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process.

Unraveling Human AQP5-PIP Molecular Interaction and Effect on AQP5 Salivary Glands Localization in SS Patients.

Saliva secretion requires effective translocation of aquaporin 5 (AQP5) water channel to the salivary glands (SGs) acinar apical membrane. Patients with Sjögren's syndrome (SS) display abnormal AQP5 localization within acinar cells from SGs that correlate with sicca manifestation and glands hypofunction. Several proteins such as Prolactin-inducible protein (PIP) may regulate AQP5 trafficking as observed in lacrimal glands from mice. However, the role of the AQP5-PIP complex remains poorly understood. In the present study, we show that PIP interacts with AQP5 in vitro and in mice as well as in human SGs and that PIP misexpression correlates with an altered AQP5 distribution at the acinar apical membrane in PIP knockout mice and SS hMSG. Furthermore, our data show that the protein-protein interaction involves the AQP5 C-terminus and the N-terminal of PIP (one molecule of PIP per AQP5 tetramer). In conclusion, our findings highlight for the first time the role of PIP as a protein controlling AQP5 localization in human salivary glands but extend beyond due to the PIP-AQP5 interaction described in lung and breast cancers.

Bimodal modulation of tau protein phosphorylation and conformation by extracellular Zn2+ in human-tau transfected cells.

Abnormal homeostasis of heavy metals is a well-documented physiopathological mechanism in Alzheimer's disease. An exacerbation of these abnormalities is best illustrated in the amyloid plaques in Alzheimer's disease brain tissue, in which zinc reaches the enormous concentration of 1000 microM. Zinc in the plaques is thought to originate from impaired glutamatergic neurons distributed in the associative cortex and limbic structures of normal brain. Although the characteristics of zinc binding to Abeta and its role in promotion of Abeta aggregation have been intensively studied, the contribution of zinc to the development of tau pathology remains elusive. To further document the effect of zinc we have investigated the modifications of tau phosphorylation, conformation and association to microtubules induced by zinc in clonal cell lines expressing a human tau isoform. A bimodal dose dependent effect of zinc was observed. At 100 microM zinc induced a tau dephosphorylation on the PHF-1 epitope, and at higher zinc concentrations induced the appearance of the abnormal tau conformational epitope MC1 and reduced the electrophoretic mobility of tau, known to be associated to increased tau phosphorylation. High zinc concentrations also increased glycogen synthase kinase-3beta (GSK-3beta) phosphorylation on tyrosine 216, a phosphorylation associated with increased activity of this tau kinase. Live imaging of tau-EGFP expressing cells demonstrated that high zinc concentrations induced a release of tau from microtubules. These results suggest that zinc plays a significant role in the development of tau pathology associated to Alzheimer's disease.

Modulation of tau pathology in tau transgenic models.

NFTs (neurofibrillary tangles) in Alzheimer's disease and in tauopathies are hallmark neuropathological lesions whose relationship with neuronal dysfunction, neuronal death and with other lesions [such as Abeta (amyloid beta-peptide) pathology] are still imperfectly understood. Many transgenic mice overexpressing wild-type or mutant tau proteins have been generated to investigate the physiopathology of tauopathies. Most of the mice overexpressing wild-type tau do not develop NFTs, but can develop a severe axonopathy, whereas overexpression of mutant tau leads to NFT formation, synaptic loss and neuronal death in several models. The association between neuronal death and NFTs has, however, been challenged in some models showing a dissociation between tau aggregation and tau toxicity. Cross-breeding of mice developing NFTs with mice developing Abeta deposits increases NFT pathology, highlighting the relationship between tau and amyloid pathology. On the other hand, tau expression seems to be necessary for expression of a pathological phenotype associated with amyloid pathology. These findings suggest that there is a bilateral cross-talk between Abeta and tau pathology. These observations are discussed by the presentation of some relevant models developed recently.