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5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease.

ABSTRACT: The 5-lipoxygenase (5LO) enzyme is upregulated in Alzheimer disease (AD), and its genetic absence reduces A? levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated.To this end, we generated triple transgenic mice (3xTg-AD) overexpressing neuronal 5LO and investigated their phenotype.Compared with controls, 3xTg-AD mice overexpressing 5LO manifested an exacerbation of memory deficits, plaques, and tangle pathologies. The elevation in A? was secondary to an upregulation of ?-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5LO-dependent tau phosphorylation, which was independent of the effect on A?.Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment.

SUBMITTER: Chu J

PROVIDER: S-EPMC3464917 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease.

Chu Jin J Giannopoulos Phillip F PF Ceballos-Diaz Carolina C Golde Todd E TE Praticò Domenico D

Annals of neurology 20120901 3

<h4>Objective</h4>The 5-lipoxygenase (5LO) enzyme is upregulated in Alzheimer disease (AD), and its genetic absence reduces Aβ levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated.<h4>Methods</h4>To this end, we generated triple transgenic mice (3xTg-AD) overexpressing neuronal 5LO and investigated their phenotype.<h4>Results</h4>Compared with controls, 3xTg-AD mice overexpressing 5LO manifested an exacerbation of memory deficits, plaques, an ...[more]

PMID: 23034916

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Project description:Characteristic features of Alzheimer's disease are memory loss, plaques resulting from abnormal processing of amyloid precursor protein (APP), and presence of neurofibrillary tangles and dystrophic neurites containing hyperphosphorylated tau. Currently, it is not known what links these abnormalities together. Cytoplasmic FMR1 interacting protein 2 (CYFIP2) has been suggested to regulate mRNA translation at synapses and this may include local synthesis of APP and alpha-calcium/calmodulin-dependent kinase II, a kinase that can phosphorylate tau. Further, CYFIP2 is part of the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein complex, which has been implicated in actin polymerization at synapses, a process thought to be required for memory formation. Our previous studies on p25 dysregulation put forward the hypothesis that CYFIP2 expression is reduced in Alzheimer's disease and that this contributes to memory impairment, abnormal APP processing and tau hyperphosphorylation. Here, we tested this hypothesis. First, in post-mortem tissue CYFIP2 expression was reduced by ?50% in severe Alzheimer's hippocampus and superior temporal gyrus when normalized to expression of a neuronal or synaptic marker protein. Interestingly, there was also a trend for decreased expression in mild Alzheimer's disease hippocampus. Second, CYFIP2 expression was reduced in old but not in young Tg2576 mice, a model of familial Alzheimer's disease. Finally, we tested the direct impact of reduced CYFIP2 expression in heterozygous null mutant mice. We found that in hippocampus this reduced expression causes an increase in APP and ?-site amyloid precursor protein cleaving enzyme 1 (BACE1) protein, but not mRNA expression, and elevates production of amyloid-?42 Reduced CYFIP2 expression also increases alpha-calcium/calmodulin-dependent kinase II protein expression, and this is associated with hyperphosphorylation of tau at serine-214. The reduced expression also impairs spine maturity without affecting spine density in apical dendrites of CA1 pyramidal neurons. Furthermore, the reduced expression prevents retention of spatial memory in the water maze. Taken together, our findings indicate that reduced CYFIP2 expression triggers a cascade of change towards Alzheimer's disease, including amyloid production, tau hyperphosphorylation and memory loss. We therefore suggest that CYFIP2 could be a potential hub for targeting treatment of the disease.

Project description:Phospho-tau 217, phospho-tau 231 and phospho-tau 181 in cerebrospinal fluid and plasma are promising biomarkers for the diagnosis of Alzheimer's disease. All these p-tau proteins are detected in neurofibrillary tangles in brains obtained post-mortem from Alzheimer's disease patients. However, increases in p-tau levels in cerebrospinal fluid and plasma during the preclinical stage of Alzheimer's disease correlate with amyloid-β burden and precede neurofibrillary tangles in brains, suggesting that these p-tau proteins are indicative of amyloid-β-mediated brain pathology. In addition, phospho-tau 217 has greater sensitivity than phospho-tau 181, though it is unclear whether each of these p-tau variants contributes to the same or a different type of neuropathology prior to neurofibrillary tangle formation. In this study, we evaluated the intracerebral localization of p-tau in App knock-in mice with amyloid-β plaques without neurofibrillary tangle pathology (AppNLGF ), in App knock-in mice with increased amyloid-β levels without amyloid-β plaques (AppNL ) and in wild-type mice. Immunohistochemical analysis showed that phospho-tau 217 and phospho-tau 231 were detected only in AppNLGF mice as punctate structures around amyloid-β plaques, overlapping with the tau pathology marker, AT8 epitope phospho-tau 202/205/208. Moreover, phospho-tau 217 and phospho-tau 202/205/208 colocalized with the postsynaptic marker PSD95 and with a major tau kinase active, GSK3β. In contrast and similar to total tau, phospho-tau 181 signals were readily detectable as fibre structures in wild-type and AppNL mice and colocalized with an axonal marker neurofilament light chain. In AppNLGF mice, these phospho-tau 181-positive structures were disrupted around amyloid-β plaques and only partially overlapped with phospho-tau 217. These results indicate that phospho-tau 217, phospho-tau 231 and a part of phospho-tau 181 signals are markers of postsynaptic pathology around amyloid-β plaques, with phospho-tau 181 also being a marker of axonal abnormality caused by amyloid-β burden in brains.

Dataset Information

5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease.

Publications

5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease.

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