Coalitions on mental health and aging: lessons learned for policy and practice.

Elders with mental health needs have been poorly served. Private and government agencies have given this issue a low priority, which is reflected in service delivery and funding. Coalitions have developed in states around the country and have engaged in a variety of tasks, including training techniques and collaborative efforts to advocate successfully for appropriate services.

Platelet amyloid precursor protein processing: a bio-marker for Alzheimer's disease.

The amyloid precursor protein (APP) in brain is processed either by an amyloidogenic pathway by beta-secretase and gamma-secretase to yield Abeta (beta-amyloid 4 kDa) peptide or by alpha-secretase within the beta-amyloid domain to yield non-amyloidogenic products. We have studied blood platelet levels of a 22-kDa fragment containing the Abeta (beta-amyloid 4 kDa) peptide, beta-secretase (BACE1), alpha-secretase (ADAM10), and APP isoform ratios of the 120-130 kDa to 110 kDa peptides from 31 Alzheimer's disease (AD) patients and 10 age-matched healthy control subjects. We found increased levels of Abeta4, increased activation of beta-secretase (BACE1), decreased activation of alpha-secretase (ADAM10) and decreased APP ratios in AD patients compared to normal control subjects.

Correlation of statin-increased platelet APP ratios and reduced blood lipids in AD patients.

Platelets, like neurons, contain 120- to 130- and 110-kd amyloid precursor proteins (APPs). Their ratio is reduced in AD, further reductions correlating with reduced Mini-Mental Status Examination scores [r(11) = 0.69, p < 0.

Platelet APP isoform ratios in asymptomatic young adults expressing an AD-related presenilin-1 mutation.

The Alzheimer's disease (AD) related amyloid precursor protein (APP) is stored, cleaved and released similarly from neurons and from platelets. We have reported that the proportion of 120-130 to 110 kDa carboxyl-cleaved APP present in the platelets of AD patients is significantly lower than that of platelets of age-matched controls. This reduced APP isoform ratio, not seen in several other disease groups, is further reduced as the severity of AD increases.

Platelet APP isoform ratios correlate with declining cognition in AD.

Background: Platelets and neurons both contain large quantities of two carboxyl-truncated 120 to 130 and 110 kDa Alzheimer amyloid precursor proteins (APPs). Platelets taken from patients with AD have been reported to contain a reduced ratio of these APPs.

Objective: To further study the AD specificity of reduced platelet APP ratios and to determine whether, after 3 years, cognitive losses in AD are accompanied by similarly reduced platelet APP ratios.

Altered apolipoprotein E secretion in cytokine treated human astrocyte cultures.

Apolipoprotein E (ApoE), postulated to be a major lipid carrier protein in brain, is synthesized and secreted primarily by astrocytes and is involved in brain development and repair. We have analyzed its secretion in primary cultures of older (high passage) slowly dividing and younger (lower passage) rapidly dividing fetal human astrocytes exposed to various inflammatory and anti-inflammatory cytokines, alone and in combination. ApoE secretion was reduced in high passage astrocytes when compared to lower passage astrocytes.

An AP-2 binding sequence within exon 1 of human and porcine choline acetyltransferase genes enhances transcription in neural cells.

The gene for choline acetyltransferase, synthesizing acetylcholine, is induced by several neurotrophic factors. A role for AP-2 in enhancing this transcription and limiting it to neural cells is strongly suggested. Previous studies demonstrated that base pairs +465-727 within the untranslated exon 1 of the porcine gene enhanced the expression of a reporter gene transfected into PC-12 cells.

Altered amyloid protein processing in platelets of patients with Alzheimer disease.

Background: beta-Amyloid peptide, the core component of neuritic plaques in brain areas in patients with Alzheimer disease (AD), is 1 cleavage product of the beta-amyloid precursor protein (APP) in neurons and platelets. Alternate cleavage products of intact 140- to 150-kd APPs in platelets include nonamyloidogenic 120- to 130-kd and 110-kd isoforms. The possible differential significance of these 2 isoforms, structurally similar to protease nexin II, is unknown.

A cell type-specific silencer in the human choline acetyltransferase gene requiring two distinct and interactive E boxes.

We have previously reported that cholinergic neuron-specific expression of the human choline acetyltransferase gene is mediated by two co-operative silencers. We have now localized the proximal silencer to the region from nucleotide -2195 to -2409, which contains two distinct E boxes (CACCTG and CATGTG). Deletion or mutation of either of these E boxes results in a loss of silencer activity.

Cholinergic neuron-specific expression of the human choline acetyltransferase gene is controlled by silencer elements.

Choline acetyltransferase (ChAT) is specifically expressed in cholinergic neurons. To identify control mechanisms regulating the cell-specific expression of the gene encoding ChAT, transient expression of the luciferase gene driven by human ChAT gene 5'flanking sequences was compared in cholinergic and noncholinergic cell lines. Analysis of the gene indicated the presence of two regulatory elements with selective silencing activity.

Morphological differentiation and proteoglycan synthesis regulate Alzheimer amyloid precursor protein processing in PC-12 and human astrocyte cultures.

A morphologically differentiated strain of rat pheochromocytoma (PC-12H) metabolically labeled with [35S]methionine and incubated with a phorbol ester displayed reduced 140-kDa and increased 15 kDa bands relative to cells incubated without phorbol ester after immunoprecipitation with antisera elicited by the C-terminal peptide of the Alzheimer amyloid precursor protein (APP). These bands correspond to glycosylated full length APP and a C-terminal fragment previously reported by Anderson et al. (Neurosci.

Increased release of an amyloidogenic C-terminal Alzheimer amyloid precursor protein fragment from stressed PC-12 cells.

Amyloid plaques, found in characteristically large numbers in specific brain areas of Alzheimer's disease (AD) and Down's Syndrome (DS) patients, are composed of a 41-43 amino acid peptide, A4, derived from a transmembrane glycoprotein, amyloid precursor protein (APP). In transformed cells APP has been shown to be cleaved within the extracellular portion of the A4 region causing the release of 100-120 kDa soluble N-terminal APP products. If this cleavage occurs in human tissue, neither the soluble product nor the remaining 10-12 kDa transmembrane fragment could be further degraded to yield A4.

Frequent alterations of specific reiterated DNA sequence abundances in human cancer.

An in-gel renaturation method allows the visualization, quantitation, and initial characterization of reiterated DNA restriction fragments (RRFs) without prior possession of their probes. Using this method we analyzed EcoRI restricted DNAs from ten human tumors, paired normal tissues from these patients, ten unpaired tumors, and 26 noncancer patients. Frequent qualitative and quantitative differences in the relative radioactive intensities of all or specific RRFs in the DNA from different individuals have been observed.

Thymidylate synthase gene amplification in fluorodeoxyuridine-resistant mouse cell lines.

We have previously isolated fluorodeoxyuridine-resistant mouse fibroblast (LU3-7) and neuroblastoma (FUdR-R) cell lines that overproduce thymidylate synthase and the mRNA for this enzyme up to 50-fold as compared to the parental cell lines. We have also cloned cDNA corresponding to mouse thymidylate synthase mRNA into pBR322. In the present study, we used this cloned cDNA as a hybridization probe in Southern blot analysis of DNA from the parental and overproducing cell lines.

Joseph disease and Huntington disease: protein patterns in fibroblasts and brain.

Proteins were separated on two-dimensional acrylamide gels obtained from brain samples of patients with Joseph disease, Huntington disease (HD) and multiple sclerosis. Similar protein separations were made from cultured skin fibroblasts of Joseph disease patients. Two major classes of proteins, one with a MW of 50,000 probably representing the glial filamentous acidic protein, or another class with a MW of 40,000 (proteins Jc, Jd, L1 and L2) were increased in the cerebellum of six Joseph disease patients.

Correlation of double-minute chromosomes with unstable multidrug cross-resistance in uptake mutants of neuroblastoma cells.

A series of increasingly drug-resistant cell populations were selected and cloned from C-46 murine neuroblastoma with the chemotherapeutic drugs maytansine, vincristine, adriamycin, or Baker's antifol. All clones demonstrated reciprocal cross-resistance to these structurally and functionally diverse drugs and failed to accumulate radiolabeled vincristine, colchicine, or Baker's antifol despite normal drug binding to cell homogenates. Initial isolates of drug-resistant populations were genetically unstable, rapidly reverting to a drug-sensitive phenotype when grown without drug, at 0.

Cyclic adenosine 3':5'-monophosphate-binding protein, a biochemical marker of neuroblastoma differentiation.

Mouse neuroblastoma tumors show reduced amounts of cyclic adenosine 3':5'-monophosphate (cAMP) binding protein. However, the levels of cAMP-binding protein were increased by 2-fold when the tumor cells were established in tissue culture, and these levels were comparable to that found in mouse brain. This binding protein is a free cAMP-binding protein that is not associated with protein kinase.

Phosphorus 31 NMR of neuroblastoma clonal lines. Effect of cell confluency state and dibutyryl cyclic AMP.

Phosphorus nuclear magnetic resonance is used to study changes in the levels of the major phosphate-containing intermediary metabolites concomitant with induced cellular differentiation in the N-18 and C-46 neuroblastoma clonal lines. The study reveals differences between the 31P-NMR profiles of the two clonal lines and also striking differences attendant to dibutyryl cAMP-mediated morphological differentiation in the N-18 clone. Phosphorus-31 NMR would appear to provide a new technique with which to study genetic differentiation.

Joseph disease: protein patterns in fibroblasts and brain.

The separation of brain and fibroblast proteins was analyzed on two-dimensional acrylamide gels. Proteins were examined from skin fibroblast cultures and brain homogenates from the frontal cerebral cortex, putamen, and cerebellum. Protein species from skin fibroblast cultures of controls and patients with Joseph disease or Huntington disease were not significantly different.