A candidate gene for the chromosome 1 Alzheimer's disease (AD) locus was identified (STM2). The predicted amino acid sequence for STM2 is homologous to that of the recently cloned chromosome 14 AD gene (S182). A point mutation in STM2, resulting in the substitution of an isoleucine for an asparagine (N141l), was identified in affected people from Volga German AD kindreds. This N141l mutation occurs at an amino acid residue that is conserved in human S182 and in the mouse S182 homolog. The presence of missense mutations in AD subjects in two highly similar genes strongly supports the hypothesis that mutations in both are pathogenic.

The cortical deposition of A␤ is an event that occurs in Alzheimer's disease, Down's syndrome, head injury, and normal aging. Previously, in appraising the effects of different neurochemical factors that impact upon the solubility of A␤, we observed that Zn 2؉ was the predominant bioessential metal to induce the aggregation of soluble A␤ at pH 7.4 in vitro and that this reaction is totally reversible with chelation. We now report that unlike other biometals tested at maximal biological concentrations, marked Cu 2؉ -induced aggregation of A␤ 1-40 emerged as the solution pH was lowered from 7.4 to 6.8 and that the reaction was completely reversible with either chelation or alkalinization. (20), amyloid Pcomponent (21), and apolipoprotein E (22, 23), A␤ is found in the brains of individuals affected by AD and Down's syndrome (DS) as dense extracellular deposits of twisted ␤-pleated sheet fibrils in the neuropil (senile plaques) and within cerebral blood vessels (amyloid congophilic angiopathy; see Refs. 4 and 5). The deposition of A␤, however, is not confined to the brain parenchyma, having been detected in amyloid diseases of the muscle (24 -26), blood vessels (27, 28), and in the kidneys, lungs, skin, subcutaneous tissue, and intestine of AD patients (29,30). Cerebral A␤ deposition occurs in other aged mammals that have the human A␤ sequence (31) but is not a feature of aged rats (32, 33). Although soluble A␤ 1-40 is produced by rat neuronal tissue (34), it contains three amino acid substitutions (Arg 3 Gly, Tyr 3 Phe, and His 3 Arg at positions 5, 10, and 13, respectively (32)) that appear to alter the physicochemical properties of the peptide preventing it from precipitating in the neocortex.A␤ accumulates in the brain in AD and DS in forms that can be resolubilized in water (35, 36) but also in forms that require harsher conditions to extract and exhibit associated SDS-resistant polymerization on polyacrylamide gel electrophoresis (35, 37). A␤ 1-40 is the predominant soluble species in biological fluids, whereas A␤ 1-42 , a minor species of A␤ that is more insoluble in vitro, is the predominant species found in plaques and deposits associated with .We have pursued studies of the physicochemical properties of synthetic A␤ peptides in order to appraise the potential of various neurochemical environments to induce A␤ deposition. To this end, we had previously found that A␤ is strikingly precipitated by certain metals in vitro, in particular Zn 2ϩ (42)(43)(44)(45). This is important since zinc and other biometals are concentrated in the brain neocortical parenchyma. A recent study, using micro particle-induced x-ray emission analyses of the cortical and accessory basal nuclei of the amygdala, demonstrated that levels of Zn 2ϩ , Fe 3ϩ , and Cu 2ϩ are significantly elevated within AD neuropil compared with control neuropil and that these metal ions are significantly further concentrated within the core and periphery of plaque deposits (46). We have also found that the extraction of A␤ deposits from brain tissue int...

Wilson disease (WD) is an autosomal recessive disorder characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain. As shown in the accompanying paper, linkage disequilibrium & haplotype analysis confirmed the disease locus to a single marker interval at 13q14.3. Here we describe a partial cDNA clone (pWD) which maps to this region and shows a particular 76% amino acid homology to the Menkes disease gene, Mc1. The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease-specific mutations, provide convincing evidence that pWD is the Wilson disease gene.

Familial Alzheimer's disease (FAD) is a genetically heterogeneous disorder that includes a rare early-onset form linked to mutations in the amyloid b protein precursor (APP) gene. Clues to the function of APP derive from the recent finding that it is a member of a highly conserved protein family that includes the mammalian amyloid precursor-like protein (APLP1) gene which maps to the same general region of human chromosome 19 linked to late-onset FAD. Here we report the isolation of the human APLP2 gene. We show that APLP2 is a close relative of APP and exhibits a very similar pattern of expression in the brain and throughout the body. Like APP, APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o) indicating that it may be an additional cell surface activator of this G protein.