Phosphodiesterase 4D (PDE4D) is one of the four PDE4 subfamilies (A/B/C/D), which specifically hydrolyse cyclic 3',5' adenosine monophosphate (cAMP) to AMP. A single gene (PDE4D; human locus 5p12) encodes a series of 11 splice variants that are generated by alternative mRNA splicing. Each isoform is characterized by a unique amino-terminal region, and the isoforms can be grouped into the so-called 'long', 'short' and 'super-short' categories. Unique to the PDE4 family are the upstream conserved region 1 (UCR1) and UCR2 modules, which influence the functional outcome of phosphorylation of the catalytic unit of PDE4B/C/D-family enzymes by the mitogen activated protein kinase Erk, with the activity of long isoforms being inhibited, short isoforms activated and super-short isoforms unaffected....MedWorm Message: Register for MedMatcha, MedWorm's medical advertising network, and receive $5 free advertising.

Tish Tucker has raised the incredible amount of £1835 for Alzheimer’s Society by taking part in a tandem parachute jump. (Source: Alzheimers Society)

Nature Reviews Drug Discovery 9, 579 (2010). doi:10.1038/nrd3237 Author: Alisa Opar New recommendations to change the diagnostic criteria for Alzheimer's disease and recent advances in biomarker development may allow earlier diagnosis of this disease, potentially providing key tools for drug development. (Source: Nature Reviews Drug Discovery)

In this study, we examined mRNA and protein expression, as well as biological activity of NEP, IDE, and ECE-1 in human frontal cortex by real-time RT-PCR for mRNA, immunoblotting for protein, and highly sensitive and specific fluorescence assays for activity. The relationships between A[beta]-degrading enzymes and pathologic measures and clinical features were also assessed. The results showed that NEP mRNA, protein level, and activity were decreased in AD compared with normal controls with no cognitive impairment (NCI). In contrast, IDE activity was unchanged, but there was higher expression of IDE mRNA, indicating a possible compensatory reaction because of deficits in activity. ECE-1 expression in AD brain showed no significant difference compared with age-matched controls. Correlation ...

In this study, we determined regional atrophy within the basal forebrain in 21 patients with AD and 16 subjects with MCI compared to 20 healthy elderly subjects using deformation-based morphometry of MRI scans. We assessed effects of basal forebrain atrophy on fiber tracts derived from high-resolution diffusion tensor imaging (DTI) using tract-based spatial statistics. We localized significant effects relative to a map of cholinergic nuclei in MRI standard space as determined from a postmortem brain. Patients with AD and MCI subjects showed reduced volumes in basal forebrain areas corresponding to anterior medial and lateral, intermediate and posterior nuclei of the Nucleus basalis of Meynert (NbM) as well as in the diagonal band of Broca nuclei (P

Authors: Skoulakis EM, Mudher A Tauopathies are a clinically diverse group of neurodegenerative dementias involving perturbations of the level or phosphorylation state of the microtubule-binding axonal protein tau. Despite intense effort in recent years, the precise role of tau in the pathology of the various behaviourally and neuropathologically distinct tauopathies, the mechanisms of tau toxicity and the potential functional interaction of tau and amyloid in Alzheimer's disease remain elusive. Nevertheless, novel observations regarding the various aspects of taumisregulation-dependent pathogenesis are emerging from various cellular, vertebrate and invertebrate animal models and are supported by new clinical data. This Focused Meeting brought together scientists working on tau and tau...MedWorm Message: Register for MedMatcha, MedWorm's medical advertising network, and receive $5 free advertising.

Authors: Wang Y, Garg S, Mandelkow EM, Mandelkow E Tau aggregation is a hallmark of several neurodegenerative diseases, including AD (Alzheimer's disease), although the mechanism underlying tau aggregation remains unclear. Recent studies show that the proteolysis of tau plays an important role in both tau aggregation and neurodegeneration. On one hand, truncation of tau may generate amyloidogenic tau fragments that initiate the aggregation of tau, which in turn can cause toxicity. On the other hand, truncation of tau may result in tau fragments which induce neurodegeneration through unknown mechanisms, independently of tau aggregation. Blocking the truncation of tau thus may represent a promising therapeutic approach for AD or other tauopathies. In the present paper, we summarize our d...

Authors: Iqbal K, Wang X, Blanchard J, Liu F, Gong CX, Grundke-Iqbal I Independent of the aetiology, AD (Alzheimer's disease) neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of AD and related tauopathies, is apparently required for the clinical expression of the disease and hence is a major therapeutic target for drug development. However, AD is multifactorial and heterogeneous and probably involves several different aetiopathogenic mechanisms. On the basis of CSF (cerebrospinal fluid) levels of Abeta(1-42) (where Abeta is amyloid beta-peptide), tau and ubiquitin, five different subgroups, each with its own clinical profile, have been identified. A successful development of rational therapeutic disease-modifying drugs for AD will require understanding of ...

Authors: Cowan CM, Shepherd D, Mudher A AD (Alzheimer's disease) is a neurodegenerative disorder characterized by the abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau and the misfolding and deposition of Abeta peptide. The mechanisms by which tau and Abeta become abnormal is not clearly understood, neither is it known what role either protein plays in the neurodegenerative process underlying AD. We have modelled aspects of AD in Drosophila melanogaster to shed light on these processes and to further our understanding of the relationship between tau and amyloid in this disease. PMID: 20658990 [PubMed - in process] (Source: Biochemical Society Transactions)

Authors: Laferla FM Abeta (amyloid beta-peptide) and tau are the main proteins that misfold and accumulate in amyloid plaques and NFTs (neurofibrillary tangles) of Alzheimer's disease and other neurological disorders. Historically, because plaques and NFTs accumulate in diverse cellular compartments, i.e. mainly extracellularly for plaques and intracellularly for NFTs, it was long presumed that the constituent proteins formed these lesions via unrelated pathways. Animal and cell studies over the last decade, however, have provided convincing evidence to show that Abeta can facilitate the development of tau pathology by altering several cell-dependent and -independent mechanisms. In the present article, results are reviewed from several laboratories that show that modulating Abeta patho...

Authors: Brion JP, Ando K, Heraud C, Leroy K 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...MedWorm Message: Register for MedMatcha, MedWorm's medical advertising network, and receive $5 free advertising.

Authors: Ando K, Leroy K, Heraud C, Kabova A, Yilmaz Z, Authelet M, Suain V, De Decker R, Brion JP We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30xTauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30xTauKO mice express fewer tau pr...

Authors: Landrieu I, Leroy A, Smet-Nocca C, Huvent I, Amniai L, Hamdane M, Sibille N, Buée L, Wieruszeski JM, Lippens G NMR spectroscopy was used to explore the different aspects of the normal and pathological functions of tau, but proved challenging because the protein contains 441 amino acids and has poor signal dispersion. We have set out to dissect the phosphorylation patterns of tau in order to understand better its role in the aggregation process and microtubule-binding regulation. Our current knowledge on the functional consequences of specific phosphorylations is still limited, mainly because producing and assessing quantitatively phosphorylated tau samples is far from straightforward, even in vitro. We use NMR spectroscopy as a proteomics tool to characterize the phosphoryl...

Authors: Pooler AM, Hanger DP Tau is an abundant microtubule-associated protein which regulates the stability of the cytoskeleton. Tau binds microtubules directly through microtubule-binding domains in its C-terminus. However, tau is not only located in the cytosol of cells, but also associated with other intracellular domains, including the plasma membrane, suggesting that tau may have additional functions other than stabilizing the neuronal cytoskeleton. Localization of tau at the cell surface appears to be dependent on interactions of the N-terminal projection domain of tau. Furthermore, membrane-associated tau is dephosphorylated at serine/threonine residues, suggesting that the phosphorylation state of tau regulates its intracellular trafficking. Dephosphorylation of tau may incre...

Authors: Leoni V, Solomon A, Kivipelto M Brain neurons remove the excess of cholesterol via conversion into the more polar 24OHC [(24S)-hydroxycholesterol]. 24OHC acts as a signalling molecule inducing ApoE (apolipoprotein E)-mediated cholesterol efflux from astrocytes, by a direct effect on ApoE transcription, protein synthesis and secretion. In CSF (cerebrospinal fluid) collected form from patients with cognitive impairment (Alzheimer's disease and patients with mild cognitive impairment) the levels of ApoE, tau, p-tau (hyperphosphorylated tau) were significantly increased, together with 24OHC, compared with controls. We also found that the levels of tau and p-tau were significantly correlated with ApoE and 24OHC in the same samples. Such a correlation was not found in control patien...

Authors: Bonda DJ, Mailankot M, Stone JG, Garrett MR, Staniszewska M, Castellani RJ, Siedlak SL, Zhu X, Lee HG, Perry G, Nagaraj RH, Smith MA Tryptophan metabolism, through the kynurenine pathway, produces neurotoxic intermediates that are implicated in the pathogenesis of Alzheimer's disease. In particular, oxidative stress via 3-hydroxykynurenine (3-HK) and its cleaved product 3-hydroxyanthranilic acid (3-HAA) significantly damages neuronal tissue and may potentially contribute to a cycle of neurodegeneration through consequent amyloid-beta accumulation, glial activation, and up-regulation of the kynurenine pathway. To determine the role of the kynurenine pathway in eliciting and continuing oxidative stress within Alzheimer's diseased brains, we used immunocytochemical methods to sho...MedWorm Message: Register for MedMatcha, MedWorm's medical advertising network, and receive $5 free advertising.

England and Leeds Carnegie rugby player Hendre Fourie called for runners in Yorkshire to raise funds for Alzheimer's Society in the Bupa Great Yorkshire Run. (Source: Alzheimers Society)

People who experience rapid eye movement sleep behaviour disorder (RBD) may go on to develop conditions such as dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy. The researchers studied the medical records of 27 people with these three neurodegenerative conditions who had also experienced RBD earlier in life. Thestudy, published in the online issue of Neurology, found that 63% of people who experienced RBD developed dementia with Lewy bodies or Parkinson's disease in later life... (Source: Health News from Medical News Today)

Although their genetic underpinnings differ, Alzheimer's disease, Parkinson's disease and Huntington's disease are all characterized by the untimely death of brain cells. What triggers cell death in the brain? According to a new study published by researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) in the July 30 issue of Molecular Cell, the answer in some cases is the untimely transfer of a gaseous molecule (known as nitric oxide, or NO) from one protein to another... (Source: Health News from Medical News Today)

Researchers have uncovered new clues about the cause of brain cell death in neurodegenerative disorders such as Parkinson's, Alzheimer's and Huntington's diseases. (Source: ScienceDaily Headlines)