Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein

Article Abstract:

Pathological examination of the brains of patients with Alzheimer's disease (AD) reveals characteristic tangles of neurofibrils, the loss of neurons, and the presence of amyloid plaques. The main constituent of the amyloid plaques is beta/A4 amyloid. This substance is derived from the cleavage of a normal cellular protein, amyloid precursor protein or APP. Many researchers have suspected that the gradual accumulation of beta/A4 eventually harms nearby neurons and is responsible for many of the pathological features of Alzheimer's disease. Using transgenic mice, strong evidence has now been obtained to indicate that this may indeed be the case. Using the techniques of genetic engineering, a fragment of the human APP gene was inserted into mouse eggs, and mice containing the gene fragment were raised. The specific APP fragment used was from the so-called C-terminus of the protein; this fragment includes the portion coding for the beta/A4 protein fragment. The transplanted gene began to express itself on day 15, and by 2 months after birth large amounts of the APP fragment were being consistently produced within the mouse's brain cells. Microscopic examination of the mouse brains at four months of age, healthy young adulthood for a mouse, revealed the presence of diffuse deposits of amyloid. By eight months of age, still relatively young for a mouse, severe pathology was present. Pathological findings included dense plaques and neurofibrillary tangles, the typical findings of Alzheimer's disease. Special genetic techniques were used to ensure that the transplanted gene fragment would be expressed in the brains of the mice and not elsewhere. This highly artificial state of genetic affairs cannot be considered directly comparable to human Alzheimer's disease. Nevertheless, the pathological observations made in these mice appear to indicate that the accumulation of fragments of APP may play a central role in pathogenesis of Alzheimer's disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Formation of beta-amyloid protein deposits in brains of transgenic mice

Article Abstract:

Patients with Alzheimer's disease have deposits of the molecule beta-amyloid in their brains. Beta-amyloid is formed from the beta-amyloid precursor protein (beta-APP). There are various forms of beta-APP; some contain genetic information that allows it to be broken down by other proteins, and others contain information that inhibits this breakdown. Transgenic mice (mice that received foreign genetic material during the embryonic stage of development) were genetically engineered to contain large amounts of the form of beta-APP that inhibits the breakdown of proteins. This results in the accumulation of beta-amyloid in various regions of the brain of the transgenic mice, similar to what is seen in patients with Alzheimer's disease. This study suggests a mechanism for beta-amyloid accumulation in the brain, which is associated with Alzheimer's disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Development and progression, Protease inhibitors, Amyloidosis

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Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors

Article Abstract:

The protein kinase C-induced phosphorylation of the threonine residue at position 840 in mGluR5a causes Ca2+ oscillations in mGluR5a-expressing cells. Glutamate produces single-peak mobilization of intracellular Ca2+ in mGluR1-alpha-transfected cells and Ca2+ oscillations in mGluR5a-transfected cells. These patterns are dependent upon the identity of a single amino acid, aspartate or threonine, which is found in the G-protein-interacting domains of mGluR1-alpha and mGluR5a, respectively.

Analysis, Observations, Glutamate, Phosphorylation, Calcium in the body, Calcium (Nutrient)

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