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Of all forms of dementia, Alzheimer''s disease is the most prevalent. It is histopathologically characterized by β-amyloid-containing plaques, tau-containing neurofibrillary tangles, reduced synaptic density and neuronal loss in selected brain areas. For the rare familial forms of Alzheimer''s disease, pathogenic mutations have been identified in both the gene encoding the precursor of the Aβ peptide, APP, itself and in the presenilin genes which encode part of the APP-protease complex. For the more frequent sporadic forms of Alzheimer''s disease, the pathogenic trigger has not been unambiguously identified. Whether Aβ is again the main cause remains to be heavily discussed. In a related disorder termed frontotemporal dementia, which is characterized by tangles in the absence of β-amyloid deposition, mutations have been identified in tau which also lead to neurodegeneration and dementia.For Alzheimer''s disease the existence of familial forms lead to the proposition of the amyloid cascade hypothesis, which claims that β-amyloid causes or enhances the tangle pathology. In this review, we describe tau transgenic mouse models in which aspects of the tau-associated pathology, including tangle formation, has been achieved. Moreover, tau transgenic mouse and tissue-culture models were used to test the amyloid cascade hypothesis. In addition, we discuss alternative hypotheses to explain the sporadic forms. The animal and tissue-culture models will provide insight into the underlying biochemical mechanisms of tau aggregation and nerve cell degeneration. These mechanisms may be partially shared between sporadic Alzheimer''s disease, the familial forms and frontotemporal dementia. Eventually, Alzheimer''s disease may be redefined based on biochemical events rather than phenotype. [Copyright &y& Elsevier]

Alzheimer’s disease (AD) is a neurogenetic condition that affects the processes via which the brain functions. Major observable hallmarks of AD are accumulated clusters of proteins in the brain. These clusters, termed neurofibrillary tangles (NFT), resemble pairs of threads wound around each other in a helix fashion accumulating within neurons. These tangles consist of a protein called Tau, which binds to tubulin, thus forming microtubules. Unlike NFTs, deposits of amyloid precursor protein (β-APP) gather in the spaces between nerve cells. The nearby neurons often look swollen and deformed, and the clusters of protein are usually accompanied by reactive inflammatory cells, microglia, which are part of the brain’s immune system responsible for degrading and removing damaged neurons or plaques. Since phosphorylation/dephosphorylation mechanisms are crucial in the regulation of Tau and β-APP, a superfamily of mitogen-activated protein kinases (MAPKs) has recently emerged as key regulators of the formation of plagues, eventually leading to dementia and AD. The complex molecular interactions between MAPKs and proteins (plagues) associated with the evolution of AD form a cornerstone in the knowledge of a still burgeoning field of neurodegenerative diseases and ageing. This review overviews current understanding of the molecular pathways related to MAPKs and their role in the development of AD and, possibly, dementia. MAPKs, therefore, may constitute a neurogenetic, therapeutic target for the diagnosis and evolution of a preventative medical strategy for early detection, and likely treatment, of Alzheimer’s. [Copyright &y& Elsevier]

Microtubule-associated protein tau is abnormally hyperphosphorylated, glycosylated, and aggregated in affected neurons in the brains of individuals with Alzheimer’s disease (AD). We recently found that the glycosylation might precede hyperphosphorylation of tau in AD. In this study, we investigated the effect of glycosylation on phosphorylation of tau catalyzed by cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase-3β (GSK-3β). The phosphorylation of the longest isoform of recombinant human brain tau, tau441, at various sites was detected by Western blots and by radioimmuno-dot-blot assay with phosphorylation-dependent and site-specific tau antibodies. We found that cdk5 phosphorylated tau441 at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3β phosphorylated all the cdk5-catalyzed sites above except Ser-235. Deglycosylation by glycosidases depressed the subsequent phosphorylation of AD-tau (i) with cdk5 at Thr-181, Ser-199, Ser-202, Thr-205, and Ser-404, but not at Thr-212; and (ii) with GSK-3β at Thr-181, Ser-202, Thr-205, Ser-217, and Ser-404, but not at Ser-199, Thr-212, Thr-231, or Ser-396. These data suggest that aberrant glycosylation of tau in AD might be involved in neurofibrillary degeneration by promoting abnormal hyperphosphorylation by cdk5 and GSK-3β. [Copyright &y& Elsevier]

Seladin-1 is a gene recently shown to be down-regulated in brain regions selectively degenerated in Alzheimer’s disease. The sequence of seladin-1 shares similarities with flavin-adenine-dinucleotide-dependent oxidoreductases and it has been found to protect cells from apoptotic cell death. In this work, we show that the transcription of seladin-1 is selectively down-regulated in the brain areas affected in Alzheimer’s disease. The down-regulation in seladin-1 transcription was associated with hyperphosphorylated tau seen as linkage to immunohistochemically detected paired helical filament tau, neuritic plaques and neurofibrillary tangles. In contrast, no association was found between seladin-1 transcription and β-amyloid deposition when analyzing human samples or tissue from transgenic animals. Furthermore, the relative transcription of seladin-1 was found to fluctuate during aging in the transgenic mouse model of Alzheimer’s disease. The fluctuation was enhanced by Alzheimer’s disease causing mutations in presenilin-1 and amyloid precursor protein genes. Finally, seladin-1 transcription was found to be up-regulated in mouse N2a cells induced to undergo apoptosis with okadaic acid.The results presented here indicate that seladin-1 transcription is selectively down-regulated in brain regions vulnerable to Alzheimer’s disease and this down-regulation is associated with the hyperphosphorylation of tau protein. [Copyright &y& Elsevier]

We report here that aggregated β-amyloid (Aβ) 1–42 promotes tau aggregation in vitro in a dose-dependent manner. When Aβ-mediated aggregated tau was used as a substrate for tau protein kinase II (TPK II), an 8-fold increase in the rate of TPK II-mediated tau phosphorylation was observed. The extent of TPK II-dependent tau phosphorylation increased as a function of time and Aβ 1–42 concentration, and hyperphosphorylated tau was found to be decorated with an Alzheimer’s disease-related phosphoepitope (P-Thr-231). In HEK 293 cells co-expressing CT-100 amyloid precursor protein and tau, the release of Aβ 1–42 from these cells was impaired. Taken together, these in vitro results suggest that Aβ 1–42 promotes both tau aggregation and hyperphosphorylation. [Copyright &y& Elsevier]