Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1996-08-23
1999-11-30
Stanton, Brian R.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435325, 435368, 435 4, G01N 3353, C12Q 100, C12N 500, C12N 508
Patent
active
059940840
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to cell and animal models of Alzheimer's disease.
Alzheimer's disease is the most common form of senile dementia, affecting approximately 5% of individuals over 65 and 20% of those over 80. It has been estimated that there are between 2.5 and 3 million patients suffering from Alzheimer's disease in the USA and 0.6 million in the UK. These figures have been projected to increase by 20% over the next 20 years as the proportion of elderly in the population increases. As yet, there are no effective treatments for Alzheimer's disease. The development to market of a therapeutic intervention for this major human disease therefore represents a significant commercial opportunity.
Alzheimer's disease is a neurodegenerative disorder characterised histopathologically by the loss of particular groups of neurones and the appearance of two principal lesions within the brain termed neurofibrillary tangles and senile plaques (Brion, 1992).
The mechanisms that result in neuronal loss are not fully understood. The discovery of several different mutations in the gene for the amyloid precursor protein (APP) in some pedigrees with familial Alzheimer's disease has given support to the "amyloid cascade" hypothesis in which the extracellular deposition of .beta.-amyloid is an early pathogenic event (see Hardy and Allsop, 1991; Selkoe, 1993; and Mattson et al. 1993 for reviews). While aberrant APP metabolism and deposition of .beta.-amyloid are currently regarded as a primary pathogenic event, there is still, however, no consensus on how deposition of .beta.-amyloid in the brain results in neurodegeneration and hence, dementia.
On the other hand, neurones containing neurofibrillary tangles almost certainly are unable to function normally and many such neurones die, as is evident from the presence of "ghost" tangles in Alzheimer brain which are the residue of dead tangle-bearing neurones.
Neurofibrillary tangles are intracellular inclusion bodies which comprise filamentous aggregates of paired helical filaments (PHF) (Lovestone and Anderton, 1992). The principal component of PHF has been shown to be tau, a microtubule-associated protein involved in stabilising the cytoskeleton and in determining neuronal shape (Kosik and Caceres, 1991). Tau is a phosphoprotein and aberrant hyperphosphorylation of tau appears to represent one, if not the, principal mechanism for its aggregation into PHF (Lovestone and Anderton, 1992). Senile plaques are composed of an extracellular fibrillar deposit of amyloid surrounded by abnormal dystrophic neurites which also contain PHF (Lovestone and Anderton, 1992). PHF pathology may also give rise to neuropil threads. Amyloid deposits are also found in the walls of cerebral blood vessels in Alzheimer's disease (Lovestone and Anderton, 1992). Amyloid fibrils in both senile plaques and cerebral blood vessels have been shown to comprise an approximately 43 residue peptide termed .beta.-amyloid or A4. .beta.-Amyloid is derived by proteolytic cleavage from the larger precursor protein, amyloid precursor protein (APP), a membrane-spanning glycoprotein.
Animal models of Alzheimer's disease have classically involved lesioning of particular neuronal pathways but these models are acute injury models, whereas Alzheimer's and other neurodegenerative disorders are slow and progressive (Wozniak et al., 1989; Holtzman et al., 1992; Anger, 1991; Myhrer, 1993). More recent attempts to generate animal models of Alzheimer's disease have involved transgenic manipulation of the APP (Wirak et al., 1991; Quon et al., 1991; Yamaguchi et al., 1991; Kammesheidt et al., 1992). Work has focused on APP because mutations in the APP gene have been shown to be the causative genetic defect in some familial cases of Alzheimer's disease (Mullan et al., 1992; Chartier Harlin et al., 1991; Goate et al., 1991; Murrell et al., 1991) and also because all Down's syndrome patients (trisomy of chromosome 21) develop classical Alzheimer's disease pathology by their 5th decade and this is now believed to be due to overexpre
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Anderton Brian H.
Miller Christopher C.
Clark Deborah J. R.
King's College London
Stanton Brian R.
Yankwich Leon R.
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