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.One of these genes hadbeen traced some years ago to chromosome 21, which was of greatinterest because that is the chromosome involved in Down's syndrome.This syndrome is sometimes referred to as "trisomy-21 disorder,"because those afflicted with it have three rather than the normal twocopies of chromosome 21.Down's syndrome patients who survive toage thirty-five or so always show evidence of Alzheimer's disease, bothclinically and at postmortem examination.The chromosome 21 gene is called APP, because it encodes a pro-tein called amyloid precursor protein.The APP protein is foundembedded in the membranes of all cells in the body.Its normal cellu-lar function is not known, but its synthesis and processing in cells, crit-ical to understanding the pathology of Alzheimer's disease, are knownin some detail (Fig.10.2).APP is a protein composed of 726 aminoacids.After insertion into the cell membrane, APP is cleaved at aminoacid 671, liberating a soluble, smaller protein of 45 amino acids calledAPP.(The rest of the molecule remains inserted in the cell mem-Sbrane.) APP is an intermediate molecule that is normally furtherS178 THE AGING BRAINFigure 10.2.Processing of the APP protein to produce A²P molecules of variouslengths.modified to produce a 40-amino-acid final soluble product called A²P.Alzheimer's disease can be caused by overproduction of APP itselfor by mutations in the APP gene that result in the production ofslightly longer versions of A²P.Overproduction of normal APPappears to cause Alzheimer's symptoms and pathology in Down's syndrome, and overexpression of the APP gene in brain cells cultured invitro has been shown to result in the buildup of A²P-containingdeposits, resulting in neuronal cell death.Mice given an extra APPgene develop severe Alzheimer's-like brain pathology.In early-onsetdisease, specific mutations in the APP gene result in a change in theprocessing of APP that results in the production of A²P moleculesgcontaining either 41 or 42 amino acids, rather than the normal 40.These slightly longer molecules condense more readily into multi-stranded amyloid sheets that form the bulk of the material found inneuritic plaques.Although the 40-amino-acid version of A²P can alsoform amyloid sheets and cause disease when it is overproduced, the 41-and 42-amino-acid forms cause earlier and more aggressive disease.Itmay seem extraordinary that such a minor change in the processing ofa protein could have such disastrous consequences, but the body'schemistry is extremely fine-tuned.Mutations in the APP gene turn out to account for only a minorportion of early-onset disease.By far the majority of cases involvemutations in two additional genes, discovered only in the past fewyears, called presenilin-1 (PS-1; mapping to chromosome 14) and pre-179 A MEANS TO AN ENDsenilin-2 (PS-2; found on chromosome 1).These two genes are closely-related, sharing 67 percent amino-acid sequence homology in the corresponding proteins.Over thirty mutations have been found in PS-1;only two have been found so far in PS-2.The PS-1 mutations accountfor roughly three-quarters of early-onset cases.Disease induced by PS-2 is more rare, and appears to be milder and slightly later in setting in.As with APP, mutations in the presenilins are dominant and fullypenetrant, meaning that only one of the two gene copies need bemutated, and the presence of an appropriate mutation results in a100 percent certainty of disease.The presence of such mutations resultsin exactly the same phenotype as APP mutations production ofslightly longer forms of A²P and development of Alzheimer's disease.The proteins encoded by these two genes are, like the APP protein,membrane-bound and found in all cells in the body.As with APP, thenormal function of these proteins is unknown.It is also not knownhow mutations in these genes cause the production of longer A²Pmolecules or why the addition of one or two amino acids to A²Pshould enhance its precipitation in neuritic plaques.Although mutations in any of the three genes discussed above can trigger early-onsetAlzheimer's disease, 10 percent or so of presenile Alzheimer's patientsdo not show mutations in any of the three, so presumably there areadditional genes waiting to be discovered.Although we do not yet understand exactly what PS-1 and -2 do inthe body under normal circumstances, some intriguing clues havecome from studies carried out in the roundworm C.elegans.One of thegreat advantages of C.elegans for understanding the function of thehuman body is that nematodes and humans are about as far apart evo-lutionarily as any two multicellular organisms could be, havingdiverged at least 800 million years ago.Therefore, whenever we findgenes that are highly conserved between these two species, it suggeststhe genes are encoding extremely important functions, functions tooimportant to have been tampered with during evolution.It turns out that C.elegans has a gene called sel-12 that has approximately 50 percent homology with human PS-1 and -2.The sel-12gene is involved in the embryonic development of several tissues in C.elegans, including nervous system tissue.The equivalent genes havealso been identified in mice, and were found to be expressed verystrongly in the mouse brain during embryonic development, but at180 THE AGING BRAINvery low levels in the adult brain.Recently, "knockout mice" lackingthe PS-1 gene were created and mated to see whether they could produce viable offspring.The embryos of these mice barely survived untilbirth; although the cellular architecture of the brain appeared normal,there was extensive hemorrhaging in both the brain and spinal cord,suggesting that PS-1 and -2 may be important in developing nervoussystem vasculature.Given the close parallels in human and mouseembryonic development, it seems likely that these genes play a similarrole in development of the human brain.How defects in brain vasculature might translate into the defectsseen in Alzheimer's disease later in life is unclear, but further studiesof these genes and their proteins in lower animals will likely shed lighton this question.And it is quite possible that the answer may beunveiled in C.elegans itself.The fact that the majority of PS-1 mutations resulting in early-onset Alzheimer's disease affect amino acidsevolutionarily conserved in PS-1 and sel-12 led researchers to askwhether the two genes might play functionally identical roles in thesetwo widely separated species.This turns out to be the case.One of thephenotypes produced in C.elegans as a result of sel-12 mutationsaffects the ability to lay eggs.Researchers have used human PS-1 genesin a form of "gene therapy" to try to correct the C.elegans defect.Whennormal forms of human PS-1 were introduced, the defect in C.eleganswas completely repaired
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