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The amyloid precursor protein (APP) of Alzheimer's disease has been shown to stimulate neurite outgrowth in vitro. The effect of APP on neurite outgrowth can be enhanced if APP is presented to neurons in substrate-bound form, in the presence of heparan sulfate proteoglycans. To identify specific heparan sulfate proteoglycans that bind to APP, conditioned medium from neonatal mouse brain cells was subjected to affinity chromatography with recombinant APP695 as a ligand. Glypican bound strongly to the APP affinity column. Purified glypican bound to APP with an equilibrium dissociation constant of 2.8 nM and inhibited APP-induced neurite outgrowth from chick sympathetic neurons. The effect of glypican was specific for APP, as glypican did not inhibit laminin-induced neurite outgrowth. Furthermore, treatment of cultures with 4-methylumbelliferyl-beta-D-xyloside, a competitive inhibitor of proteoglycan glycanation, inhibited APP-induced neurite outgrowth but did not inhibit laminin-induced neurite outgrowth. This result suggests that endogenous proteoglycans are required for substrate-bound APP to stimulate neurite outgrowth. Secreted glypican may act to inhibit APP-induced neurite outgrowth in vivo by competing with endogenous proteoglycans for binding to APP.

The majority of cases of Alzheimer's disease are sporadic. However, there are also numerous examples of families in which Alzheimer's disease is passed from generation to generation. While the sporadic cases of Alzheimer's disease generally begin only at an advanced age, the familial cases are usually of much earlier onset. Some researchers are returning to familial cases of Alzheimer's disease with renewed interest. The authors describe the occurrence of Alzheimer's disease as an inherited trait in two large Belgian families. In both families, the disorder seems to be passed along as an autosomal dominant trait, although mapping of the gene to a particular chromosome has not yet been accomplished for these two families. (Other research has indicated that the gene is on chromosome 21.) A total of 63 affected patients occurred in the two families, and the majority first developed symptoms of Alzheimer's disease in their thirties. While the age of onset of AD for some family members is not known, an onset as early as 26 years was observed and no onset later than age 45 has been documented. The neuropathological examination of autopsy material from the first family revealed the typical neurofibrillary tangles and senile plaques associated with Alzheimer's disease. Since the second family had a greater frequency of myoclonus and pyramidal signs, there was some suggestion that the syndrome might, in fact, be Gerstmann-Straussler-Scheinker syndrome (GSS). However, neuropathological examination of autopsy specimens from this family as well showed the typical changes of Alzheimer's disease and did not show any of the spongiform changes associated with GSS. Numerous studies of Alzheimer's disease have failed to reveal a clear understanding of the underlying genetics; some authors feel that a strong genetic component is masked simply because many people carrying the putative gene do not live long enough to express it. Conversely, studies on identical twins have demonstrated that a single gene is not sufficient to explain the clinical disease. The authors emphasize that familial Alzheimer's disease provides a unique opportunity and urge that if such families are encountered, they be studied in a careful and reliable way and that blood specimens be obtained for subsequent genetic analysis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Evidence That Β-Amyloid Protein in alzheimer's Disease Is Not Derived by Normal Processing ALZHEIMER'S DISEASE (AD), THE most common form of dementia in the elderly, affects [is greater than] 10% [...]