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PubMed2003

Neuroimaging of animal models of brain disease.

The main aim of this review is to describe some of the many animal models that have proved to be valuable from a neuroimaging perspective. This paper complements other articles in this volume, with a focus on animal models of the pathology of human brain disorders for investigations with modern non-invasive neuroimaging techniques. The use of animal model systems forms a fundamental part of neuroscience research efforts to improve the prevention, diagnosis, understanding and treatment of neurological conditions. Without such models it would be impossible to investigate such topics as the underlying mechanisms of neuronal cell damage and death, or to screen compounds for possible anticonvulsant properties. The adequacy of any one particular model depends on the suitability of information gained during experimental conditions. It is important, therefore, to understand the various types of animal model available and choose an appropriate model for the research question.

Animals↗
PubMed2002

Topographic regulation of kinase activity in Alzheimer's disease brains.

At autopsy, a most distinctive pathology seen in Alzheimer's disease (AD) brains is numerous abnormal neurons filled with neurofibrillary tangles (NFTs) containing stable complexes of hyperphosphorylated tau (PHF), neurofilaments and various kinases, among other proteins. Though these neuronal aggregates have been actively studied, their nature and origin are still poorly understood. Our studies of regulation of phosphorylation in neurons of the squid giant fiber system, using P13(suc1) affinity chromatography, suggest that neuronal phosphorylation of cytoskeletal proteins is compartmentalized into active axonal and inactive cell body-specific multimeric complexes of kinases, substrates and phosphatases. To determine whether such compartment-specific phosphorylation complexes are present in human brains, we separated gray matter (enriched in cell bodies) and white matter (enriched in axons) from normal and AD brains and studied the total kinase activities in lysates, pellets and P13(suc1) complexes. In addition, Western blot analysis was used to characterize the proteins associated with P13(suc1) multimeric complexes extracted from gray and white matter. We tested the hypothesis that P13 phosphorylation complexes were abnormally compartmentalized in AD neurons with the more active complexes shifted to cell bodies (gray matter) instead of axons (white matter). We found that (1) endogenous and exogenous substrate-dependent kinase activities of AD and control brain extracts were similar in both gray and white matter. (2) Long post mortem times tend to erase any differences in kinase activity between control and AD extracts. In contrast to shorter post mortem times (4.5-10 hrs), long post mortem times (13-34 hrs) significantly minimize the variances in kinase activities between control and AD brain extracts suggesting that cell death and proteolysis may eliminate any intrinsic differences in enzyme activities. (3) Except for the significantly higher level of histone phosphorylation in control white extracts, the kinase activities of P13(suc1)-derived multimeric complexes from gray and white matter were also similar in control and AD brains. Here, too, variances between control and AD distributions were significantly different (p < 0.001-0.02) suggesting that the P13 complexes were different. We also found differences in the Western blot profiles of P13suc1-associated kinases and cytoskeletal proteins; higher expression of phosphorylated NF-H and PHF-tau in gray matter of AD brains was detected. We believe that such differences in P13 complexes from human control and AD brain samples displaying extensive heterogeneity in age, post mortem time and clinical history, may be important.

Alzheimer Disease↗
PubMed1995

[Value of Turbo-FLAIR sequence in the diagnosis of brain diseases at 0.5 tesla].

PURPOSE: Aim of the study was to evaluate FLAIR combined with Turbo-Spin-Echo (Turbo-FLAIR) at 0.5 tesla in comparison to conventional T1- and T2-weighted spin-echo images (SE) in MRI of the brain. MATERIAL AND METHODS: A Turbo-FLAIR sequence was optimised for 0.5 Tesla (Philips Gyroscan T5-II) that provided seventeen 5 mm sections in 4:21 minutes (TR = 6075 ms, T1 = 1600 ms, TE = 120 ms and a turbofactor = 17). Images were compared with T1- (TR = 500 ms, TE = 15 ms) proton density and T2-weighted spin-echo (TR = 2500 ms, TE = 20/90 ms) studies in 10 healthy volunteers and 30 patients with various brain pathologies. RESULTS: Turbo-FLAIR could effectively eliminate the CSF signal in all studies except ventricular areas with CSF inflow. Contrast-to-noise ratios (C/N) for the contrast between lesions and CSF was superior in Turbo-FLAIR. C/N between lesions and grey matter was significantly higher in Turbo-FLAIR than in proton density (PD)-weighted SE. C/N between lesions and white matter was equal to PD-weighted SE but significantly smaller than on T2-weighted SE. Visual analysis showed greater lesions conspicuity with Turbo-FLAIR and a higher frequency of detection of cortical and subcortical lesions. CONCLUSIONS: Turbo-FLAIR is a reliable and practical technique on 0.5 Tesla, that is more sensitive than SE sequences especially for the detection of cortical, subcortical lesions and lesions surrounded by CSF.

Adolescent↗
PubMed2004

Amyloid precursor protein mRNA levels in Alzheimer's disease brain.

Insoluble beta-amyloid deposits in Alzheimer's disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls (p=0.002). There was no change in the mRNA levels of KPI-(APP 695) (p=0.898). Therefore, whilst KPI-mRNA levels remained stable the KPI(+) species increased specifically in the AD brains.

Adult↗
PubMed2003

P38 MAP kinase is activated at early stages in Alzheimer's disease brain.

The regional, cellular, and subcellular localization of phosphorylated p38 MAPK (pp38) was examined by immunocytochemistry, immuofluorescent multiple labeling, and immunoblotting of extracts as well as immunoprecipitates of human postmortem tissue from control and Alzheimer's disease (AD) cases at different Braak stages. "Early AD" cases (Braak stages IV-V) and a subset of Braak stage VI cases have high levels of pp38 immunoreactivity, with the most dense immunoreactivity located in CA2 and subiculum followed by CA1 in the hippocampus. On the contrary, very little pp38 was detected in age-matched controls (Braak stages 0-II). More importantly, as revealed by various multiple labeling experiments, pp38 immunoreactivity is mainly located in neurons bearing early neurofibrillary pathology, but not in typically fibrillar tangles that are densely stained by thioflavin-S. Most pp38-positive neurons only contain a small amount of phospho-tau. Additionally, pp38 immunoreactivity was not associated with senile plaques. At the subcellular level, pp38-immunoreactive granules are usually larger than the granules stained with the lysosomal marker cathepsin D. Immunoblotting with different extraction buffers and immunoprecipitation indicate that pp38 does not or only loosely binds to phospho-tau. Taken together, this study demonstrates that p38 MAPK is activated at early stages of neurofibrillary degeneration in AD hippocampus. The p38 activation may also be linked to neurodegeneration through mechanisms other than neurofibrillary tangle formation.

Aged↗