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Biomedical subjects

Peter Davies

Publications and source records attributed to Peter Davies.

At least 55 records · Page 3Linked to original sources
PubMed2003

Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1.

Alzheimer's disease (AD) is genetically linked to the processing of amyloid beta protein precursor (AbetaPP). Aside from being the precursor of the amyloid beta (Abeta) found in plaques in the brains of patients with AD, little is known regarding the functional role of AbetaPP. We have recently reported biochemical evidence linking AbetaPP to the JNK signaling cascade by finding that JNK-interacting protein-1 (JIP-1) binds AbetaPP. In order to study the functional implications of this interaction we assayed the carboxyl-terminal of AbetaPP for phosphorylation. We found that the threonine 668 within the AbetaPP intracellular domain (AID or elsewhere AICD) is indeed phosphorylated by JNK1. We surprisingly found that although JIP-1 can facilitate this phosphorylation, it is not required for this process. We also found that JIP-1 only facilitated phosphorylation of AbetaPP but not of the two other family members APLP1 (amyloid precursor-like protein 1) and APLP2. Understanding the connection between AbetaPP phosphorylation and the JNK signaling pathway, which mediates cell response to stress may have important implications in understanding the pathogenesis of Alzheimer's disease.

Adaptor Proteins, Signal Transducing↗
PubMed2003

The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy.

We report a case of rapidly progressive frontotemporal dementia presenting at age 33 years. At autopsy there was severe atrophy of the frontal and temporal lobes. Tau-positive Pick bodies, which ultrastructurally were composed of straight filaments, were present, accompanied by severe neuronal loss and gliosis. RD3, a tau antibody specific for the three-repeat (3R) isoforms, labeled the Pick bodies. ET3, a four-repeat (4R) isoform-specific tau antibody, did not label Pick bodies, but highlighted rare astrocytes, and threads in white matter bundles in the corpus striatum. Analysis of the tau gene revealed an L266V mutation in exon 9. Analysis of brain tissue from this case revealed elevated levels of exon 10+ tau RNA and soluble 4R tau. However, both 3R and 4R isoforms were present in sarkosyl-insoluble tau fractions with a predominance of the shortest 3R isoform. The L266V mutation is associated with decreased rate and extent of tau-induced microtubule assembly, and a 3R isoform-specific increase in tau self assembly as measured by an in vitro assay. Combined, these data indicate that L266V is a pathogenic tau mutation that is associated with Pick-like pathology. In addition, the results of the RD3 and ET3 immunostains clearly explain for the first time the presence of both 3R and 4R tau isoforms in preparations of insoluble tau from some Pick's disease cases.

Adult↗
PubMed2003

Cdk5 is a key factor in tau aggregation and tangle formation in vivo.

Tau aggregation is a common feature of neurodegenerative diseases such as Alzheimer's disease, and hyperphosphorylation of tau has been implicated as a fundamental pathogenic mechanism in this process. To examine the impact of cdk5 in tau aggregation and tangle formation, we crossed transgenic mice overexpressing the cdk5 activator p25, with transgenic mice overexpressing mutant (P301L) human tau. Tau was hyperphosphorylated at several sites in the double transgenics, and there was a highly significant accumulation of aggregated tau in brainstem and cortex. This was accompanied by increased numbers of silver-stained neurofibrillary tangles (NFTs). Insoluble tau was also associated with active GSK. Thus, cdk5 can initiate a major impact on tau pathology progression that probably involves several kinases. Kinase inhibitors may thus be beneficial therapeutically.

Animals↗
PubMed2003

Pin1 colocalization with phosphorylated tau in Alzheimer's disease and other tauopathies.

Pin1, a peptidyl-prolyl isomerase binds to mitotic serine or threonine phosphoproteins. In Alzheimer's disease (AD) evidence points to the reactivation of mitosis in vulnerable neurons. Tangles composed of hyperphosphorylated tau contain phosphorylated Thr231 (pThr231 tau), which occurs to a greater extent in the AD brain than in the normal brain, and Pin1 has been shown to bind pThr231 tau. Here, Pin1 distribution in AD, and its colocalization with pThr231 tau in AD, FTDP-17 (P301L), Pick's disease (PiD), and PSP was investigated using TG-3, a monoclonal antibody to conformationally altered pThr231 tau. The Pin1 antibody A-20 detected granular Pin1 staining in AD brains, but not in normal brains. A-20 immunoreactive granules colocalized with TG-3-stained granules but not with TG-3-stained pretangles, tangles, or Pick bodies in AD, PiD, and FTDP-17 (P301L). Pin1 granules were sparse in PSP, and rarely did A-20 colocalize with TG-3. The appearance of Pin1 granules in the early stages of AD, PiD, and FTDP-17 (P301L) implicates Pin1 in their pathogenesis but not in PSP.

Alzheimer Disease↗
PubMed2003

Traditional markers of excessive alcohol use.

AIMS: The blood tests used traditionally as markers of excessive drinking are the liver enzymes, gamma glutamyltransferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and the red blood cell volume (mean corpuscular volume: MCV). Here we review the nature of these markers' association with alcohol use, their practical application in detecting, assessing or monitoring drinking and increases in understanding of these markers in the past 10 years. DESIGN: Articles were identified via Medline search and perusal of bibliographies. FINDINGS: The conventional markers have imperfect sensitivity and specificity, but have an added clinical role in the detection of complications of drinking, and of comorbid conditions that may increase risk of drinking. GGT may in part be a marker of the oxidative stress associated with ethanol metabolism. Markers are more likely to be elevated in those aged more than 30 years and in regular drinkers with a longer drinking history. The markers may be useful in opportunistic case finding, in motivating patients to change drinking and in monitoring treatment response. Increased prevalence of obesity and hepatitis C must be considered in interpretation of liver enzyme results. The liver enzymes are prognostic indicators for several medical conditions and for mortality. CONCLUSIONS: These conventional tests are widely available and relatively inexpensive. While having limited sensitivity and specificity in detection of excessive drinking, they also provide valuable data on complications of drinking, comorbid conditions that may be affected by drinking and, in some cases, prognosis.

Alanine Transaminase↗
PubMed2003

Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles.

Elevated levels of p25 and constitutive activation of CDK5 have been observed in AD brains. This has led to the hypothesis that increased p25 levels could promote neurofibrillary tangles (NFT) through CDK5-mediated hyperphosphorylation of tau, the principal component of NFTs. We examined p25 immunoreactivity in brains from sporadic and familial AD cases, as well as other neurologic diseases that exhibit NFT, such as Down's syndrome (DS), Pick's disease (Pick), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD). Neither the p25 immunoreactivity nor the p25/p35 ratio was elevated in the AD brains or in the other tauopathies (n = 34) compared with controls (n = 11). Although Abeta peptides have been suggested to activate calpain-mediated cleavage of p35 to p25 in cultured neurons, p25 levels in brains of TgCRND8 mice, which express high levels of brain Abeta peptides, were similar to those of non-Tg littermates. Our data suggest that high Abeta levels in brain do not activate p35 proteolysis, and p25 is unlikely to be a causative agent for NFT formation in AD or other tauopathies.

Adult↗
PubMed2003

Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms.

Neurofibrillary tangles are composed of insoluble aggregates of the microtubule-associated protein tau. In Alzheimer's disease the accumulation of neurofibrillary tangles occurs in the absence of tau mutations. Here we present mice that develop pathology from non-mutant human tau, in the absence of other exogenous factors, including beta-amyloid. The pathology in these mice is Alzheimer-like, with hyperphosphorylated tau accumulating as aggregated paired helical filaments. This pathologic tau accumulates in the cell bodies and dendrites of neurons in a spatiotemporally relevant distribution.

Age Factors↗
PubMed2003

Colocalization of tau and alpha-synuclein epitopes in Lewy bodies.

The major protein constituent of Lewy bodies (LBs), the pathological hallmark of Parkinson disease and dementia with Lewy bodies, is considered to be alpha-synuclein, but other proteins, in particular the microtubule-associated protein tau, have been implicated in the pathogenesis of LBs. Tau is the major structural component of neurofibrillary tangles (NFTs). Both direct immunochemical studies of partially purified LBs and indirect immunohistochemical studies have suggested that LBs may contain tau, but most of these studies were based upon a single tau antibody, and immunologic cross-reactivity was not completely excluded. To gain insight into the relation between tau and alpha-synuclein in LBs, double immunostaining was performed in Lewy body cases with a rabbit polyclonal antibody to alpha-synuclein and a panel of monoclonal antibodies to phospho- and nonphospho-tau epitopes (Alz50, CP9, CP13, PG5, TG3, PHFI) that spanned the length of the tau molecule. Tau-immunoreactive LBs were present in the medulla in 80% of the cases, irrespective of Braak stage. All tau antibodies recognized at least some LBs, arguing against nonspecific antibody cross-reactivity. In most lesions the tau immunostaining was present at the periphery of the LB. The phospho-tau antibody, TG3, detected more LBs than any of the other tau antibodies. The proportion of LBs with tau immunoreactivity was greatest in neurons vulnerable to NETs, such as those in the locus ceruleus and basal nucleus of Meynert, and least in neurons resistant to NFTs, such as the dorsal motor nucleus of the vagus in the medulla. The present results suggest that tau may coaggregate with alpha-synuclein in LBs, especially in neuronal populations vulnerable to both NFTs and LBs.

Aged↗
PubMed2003

Matrix metalloproteinase-9 expression in renal biopsies of patients with HIV-associated nephropathy.

BACKGROUND/AIMS: The normal architecture and function of the kidney are maintained by a critical turnover of the extracellular matrix (ECM). Although increased synthesis of ECM leads to progression of renal failure, the role of degradation of ECM by metalloproteinases in progressive nephropathies is unclear. Recently, in an animal model of membranous glomerulonephritis (Heymann nephritis), visceral epithelial cell (VEC) injury has been found to rapidly increase matrix metalloproteinase-9 (MMP-9) synthesis by these cells during the period of maximal proteinuria. Because injury to glomerular VECs may be an important initiating factor in the pathogenesis of focal segmental glomerulosclerosis (FSGS), especially in HIV-associated nephropathy (HIVAN), we determined the expression of MMP-9 and its inhibitors in renal biopsies of patients with HIVAN. METHODS: RNA was isolated from cortical renal tissue of 6 patients with HIVAN. Only those biopsies which displayed characteristic findings of HIVAN including collapsing FSGS, cystic dilatation of the tubules, and proliferation of VECs were used. As controls, we obtained renal cortical tissue from normal areas of kidneys removed due to malignancies. MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 mRNA expressions were determined using real-time quantitative reverse transcription-polymerase chain reaction. In all 6 patients with HIVAN, MMP-9 and TIMP-1 were overexpressed. We localized MMP-9 protein to the glomeruli with immunohistochemical detection. CONCLUSION: MMP-9 is overexpressed in the glomeruli of patients with HIVAN and may be involved in the pathogenesis of the disease.

AIDS-Associated Nephropathy↗
PubMed2002

Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model.

NPC-1 gene mutations cause Niemann-Pick type C (NPC), a neurodegenerative storage disease resulting in premature death in humans. Spontaneous mutation of the NPC-1 gene in mice generates a similar phenotype, usually with death ensuing by 12 weeks of age. Both human and murine NPC are characterized neuropathologically by ballooned neurons distended with lipid storage, axonal spheroid formation, demyelination, and widespread neuronal loss. To elucidate the biochemical mechanism underlying this neuropathology, we have investigated the phosphorylation of neuronal cytoskeletal proteins in the brains of npc-1 mice. A spectrum of antibodies against phosphorylated epitopes in neurofilaments (NFs) and MAP2 and tau were used in immunohistochemical and immunoblotting analyses of 4- to 12-week-old mice. Multiple sites in NFs, MAP2, and tau were hyperphosphorylated as early as 4 weeks of age and correlated with a significant increase in activity of the cyclin-dependent kinase 5 (cdk5) and accumulation of its more potent activator, p25, a proteolytic fragment of p35. At 5 weeks of age, the development of axonal spheroids was noted in the pons. p25 and cdk5 coaccumulated with hyperphosphorylated cytoskeletal proteins in axon spheroids. These various abnormalities escalated with each additional week of age, spreading to other regions of the brainstem, basal ganglia, cerebellum, and eventually, the cortex. Our data suggest that focal deregulation of cdk5/p25 in axons leads to cytoskeletal abnormalities and eventual neurodegeneration in NPC. The npc-1 mouse is a valuable in vivo model for determining how and when cdk5 becomes deregulated and whether cdk5 inhibitors would be useful in blocking NPC neurodegeneration.

Animals↗