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We tested the hypothesis that synaptic defects in the hippocampus of individuals with Alzheimer disease (AD) correlate with the severity of cognitive impairment. Three postmortem groups were studied: controls with normal and stable cognition; cognitively intact subjects with senile plaque densities diagnostic for possible AD (p-AD) and neurofibrillary changes characteristic of early AD (Braak stage III); and individuals with definite AD and neurofibrillary changes typical of incipient to severe AD (Braak stage III, V, or VI). Synaptophysin (a presynaptic vesicle protein) levels were quantified by immunoblotting of synaptic membrane fractions isolated from hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex. Average synaptophysin levels were reduced in hippocampus when comparing definite AD to controls (55%, p < 0.0001), p-AD to control (25%, p < 0.005), and definite AD to p-AD (30%, p < 0.05), but levels in entorhinal cortex, occipital cortex, and caudate nucleus were either unchanged or less significantly altered than in hippocampus. By univariate analysis, hippocampal synaptophysin levels correlated with neuropsychological measurements, including Mini-mental state examination scores (r = 0.83, p < 0.0001) and Blessed scores (r = 0.74, P < 0.001), and with senile plaque densities (r = 0.89, p < 0.0001). We conclude that synaptic abnormalities in the hippocampus correlate with the severity of neuropathology and memory deficit in individuals with AD, and that this defect may predate neuropsychological evidence for cognitive impairment early in AD.

Abnormal biology of [alpha]-synuclein ([alpha]-Syn) is directly implicated in the pathogenesis of Parkinson's disease and other [alpha]-synucleinopathies. Herein, we demonstrate that C-terminally truncated [alpha]-Syn ([alpha]Syn[DELTA]C), enriched in the pathological [alpha]-Syn aggregates, is normally generated from full-length [alpha]-Syn independent of [alpha]-Syn aggregation in brains and in cultured cells. The accumulation of [alpha]-Syn[DELTA]C is enhanced in neuronal cells as compared with nonneuronal cells. Significantly, the expression of familial Parkinson's disease-linked mutant [alpha]-Syn is associated with the enhanced cellular accumulation of [alpha]-Syn[DELTA]C. Moreover, substoichiometric amounts of [alpha]-Syn[DELTA]C enhance the in vitro aggregation of the more abundant full-length [alpha]-Syn. Finally, cases of [alpha]-synucleinopathy exhibit increases in the total soluble [alpha]-Syn and a higher proportion of soluble [alpha]-Syn[DELTA]C, a condition favoring the aggregation of [alpha]-Syn. Collectively, our results indicate that the biology behind the generation and accumulation of [alpha]-Syn[DELTA]C is likely to have relevance for the initiation and the progression of [alpha]-Syn aggregation in vivo. [alpha]-synucleinopathy | mass spectrometry | proteolysis | Lewy body

Cases of Alzheimer's disease involving autosomal dominant inheritance of mutations in the genes presenilin 1 (PS1) and presenilin 2 (PS2) are studied. PS1 mutations, a multipass transmembrane protein, were attributed to 25% of the cases involving familial Alzheimer's disease. This gene type is a functional homologue of a 'Caenorhabditis elegans' protein called SEL-12.

Injury-induced death of facial motor neurons in neonatal rats is inhibited by neurotrophin 4/5 (NT-4/5), a functional receptor for NT-4/5 expressed by facial motor neurons. A role as physiological survival factors for facial motor neurons is confirmed for NT-4/5 and brain-derived neurotrophin factor.

Subtype-specific antibodies used in Western blot and immunoprecipitation investigations facilitate the detection and characterization of D1 and D2 dopamine receptors in the brain. During these studies, the antibodies directed against recombinant D1 and D2 proteins adhere to the receptor subtypes. The localization of presynaptic D1 and D2 receptors, in the subsets of spiny dendrites and spine heads in rat neostriatum, suggests the regulatory role of the subsets in affecting neurotransmitter release.

Disease-related mutations in amyloid precursor proteins (APPs) or scrapic prion protein (PrPsc) increase the fibrillogenic nature of peptides in familial Alzheimer disease (AD) and the prion disorders/spongiform encephalopathies, confirming that conformational alterations in the related polypeptides are crucial to the generation of amyloid fibrils. Amyloid fibrils (approximately 8 nm) have a 4-kDa peptide (amyloid beta-protein; A beta or beta/A4) obtained from bigger APPs coded for by a gene on chromosome 21. PrPs are abnormal cellular proteins that are believed to transmit prion disorders/spongiform encephalopathies.

Significant progress has been made over recent years in identifying the genetic features of some diseases of the central nervous system and in understanding pathogenic mechanisms. It should eventually be possible to establish new therapeutic targets and to design new treatments. Researchers are now using model systems for molecular and cell biological investigations of pathogenic mechanisms and to identify new therapeutic targets. These models will be used to test new drugs.

Abstract Background Medulloblastomas, embryonal tumors arising in the cerebellum, commonly contain mutations that activate Wnt signaling. To determine whether increased Wnt signaling in the adult CNS is sufficient to induce tumor formation, we created transgenic mice expressing either wild-type or activated β-catenin in the brain. Methods Wild-type and mutant human β-catenin transgenes were expressed under the control of a murine PrP promoter fragment that drives high level postnatal expression in the CNS. Mutant β-catenin was stabilized by a serine to phenylalanine alteration in codon 37. Results Expression of the mutant transgene resulted in an approximately two-fold increase in β-catenin protein levels in the cortex and cerebellum of adult animals. Immunohistochemical analysis revealed nuclear β-catenin in hippocampal, cortical and cerebellar neurons of transgenic animals but not in non-transgenic controls. Tail kinking was observed in some transgenic animals, but no CNS malformations or tumors were detected. Conclusions No tumors or morphologic alterations were detected in the brains of transgenic mice expressing stabilized β-catenin, suggesting that postnatal Wnt signaling in differentiated neurons may not be sufficient to induce CNS tumorigenesis.

Recent studies in Saccharomyces cerevisiae suggest that the delivery of copper to Cu/Zn superoxide dismutase (SOD1) is mediated by a cytosolic protein termed the copper chaperone for superoxide dismutase (CCS). To determine the role of CCS in mammalian copper homeostasis, we generated mice with targeted disruption of CCS alleles ([CCS.sup.-/-] mice). Although [CCS.sup.-/-] mice are viable and possess normal levels of SOD1 protein, they reveal marked reductions in SOD1 activity when compared with control littermates. Metabolic labeling with [sup.64]Cu demonstrated that the reduction of SOD1 activity in [CCS.sup.-/-] mice is the direct result of impaired Cu incorporation into SOD1 and that this effect was specific because no abnormalities were observed in Cu uptake, distribution, or incorporation into other cuproenzymes. Consistent with this loss of SOD1 activity, [CCS.sup.-/-] mice showed increased sensitivity to paraquat and reduced female fertility, phenotypes that are characteristic of SOD1-deficient mice. These results demonstrate the essential role of any mammalian copper chaperone and have important implications for the development of novel therapeutic strategies in familial amyotrophic lateral sclerosis.