Alzheimer Disease: Petanceska S

Petanceska S, Ryan L, Silverberg N, Buckholtz N. · Division of Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Alzheimers Dement. · Pubmed #19328442 No free full text.

This publication has no abstract.

Pappolla MA, Smith MA, Bryant-Thomas T, Bazan N, Petanceska S, Perry G, Thal LJ, Sano M, Refolo LM. · University of South Alabama, Mobile 36617, USA. · Free Radic Biol Med. · Pubmed #12106813 No free full text.

Abstract: Recent epidemiological, clinical, and experimental data suggest that cholesterol may play a role in Alzheimer's disease (AD). We have recently shown that cholesterolemia has a profound effect in the development and modulation of amyloid pathology in a transgenic model of AD. This review summarizes recent advancements in our understanding of the potential role of cholesterol and the amyloid beta protein in initiating the generation of free radicals and points out their role in a chain of events that causes damage of essential macromolecules in the central nervous system and culminates in neuronal dysfunction and loss. Experimental data links cholesterol and oxidative stress with some neurodegenerative aspects of AD.

Gandy S, Petanceska S. · Department of Psychiatry, New York University, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg 10962, USA. · Adv Exp Med Biol. · Pubmed #11403168 No free full text.

This publication has no abstract.

Gandy S, Petanceska S. · Department of Psychiatry, New York University, Nathan S. Kline Institute for Psychiatric Research, Orangeburg 10962, USA. · Novartis Found Symp. · Pubmed #10965512 No free full text.

Abstract: Alzheimer's disease (AD) is characterized by the intracranial accumulation of the 4 kDa amyloid beta peptide (A beta), following proteolysis of a approximately 700 amino acid, integral membrane precursor, the amyloid beta precursor protein (APP). The best evidence causally linking APP to AD has been provided by the discovery of mutations within the APP coding sequence that segregate with disease phenotypes in autosomal dominant forms of familial AD (FAD). Though FAD is rare (< 10% of all AD), the hallmark features--amyloid plaques, neurofibrillary tangles, synaptic and neuronal loss, neurotransmitter deficits, dementia--are indistinguishable when FAD is compared with typical, common, 'non-familial', or sporadic AD (SAD). Studies of some clinically relevant mutant APP molecules from FAD families have yielded evidence that APP mutations can lead to enhanced generation or aggregability of A beta, consistent with a pathogenic role in AD. Other genetic loci for FAD have been discovered which are distinct from the immediate regulatory and coding regions of the APP gene, indicating that defects in molecules other than APP can also specify cerebral amyloidogenesis and FAD. To date, all APP and non-APP FAD mutations can be demonstrated to have the common feature of promoting amyloidogenesis of A beta. Epidemiological studies indicate that postmenopausal women on oestrogen hormone replacement therapy (HRT) have their relative risk of developing SAD diminished by about one-third as compared with age-matched women not receiving HRT. Because of the key role of cerebral A beta accumulation in initiating AD pathology, it is most attractive that oestradiol might modulate SAD risk or age-at-onset by inhibiting A beta accumulation. A possible mechanistic basis for such a scenario is reviewed here.

Gandy S, Petanceska S. · Department of Psychiatry, The Nathan S. Kline Institute for Psychiatric Research, New York University, Orangeburg, NY 10962, USA. · Biochim Biophys Acta. · Pubmed #10899430 No free full text.

Abstract: Alzheimer's disease (AD) is characterized by the intracranial accumulation of the 4 kDa amyloid-beta peptide (Abeta), following proteolysis of a approximately 700-amino acid, integral membrane precursor, the Alzheimer amyloid precursor protein (APP). The best evidence causally linking APP to AD has been provided by the discovery of mutations within the APP coding sequence that segregate with disease phenotypes in autosomal dominant forms of familial AD (FAD). Though FAD is rare ( < 10% of all AD), the hallmark features (amyloid plaques, neurofibrillary tangles, synaptic and neuronal loss, neurotransmitter deficits and dementia) are indistinguishable when FAD is compared with typical, common, 'non-familial', or sporadic, AD (SAD). Studies of some clinically relevant mutant APP molecules from FAD families have yielded evidence that APP mutations can lead to the enhanced generation or aggregability of Abeta, consistent with a pathogenic role in AD. Other genetic loci for FAD have been discovered which are distinct from the immediate regulatory and coding regions of the APP gene, indicating that defects in molecules other than APP can also specify cerebral amyloidogenesis and FAD. To date, all APP and non-APP FAD mutations can be demonstrated to have the common feature of promoting amyloidogenesis of Abeta. Epidemiological studies indicate that postmenopausal women on estrogen replacement therapy (ERT) have their relative risk of developing SAD diminished by about one third as compared with age-matched women not receiving ERT [M.X. Tang, D. Jacobs, Y. Stern, K. Marder, P. Schofield, B. Gurland, H. Andrews, R. Mayeux, Effect of estrogen during menopause on risk and age at onset of Alzheimer's disease, Lancet 348 (2000) 429432]. Because of the key role of cerebral Abeta accumulation in initiating AD pathology, it is most attractive that estradiol might modulate SAD risk or age-at-onset by inhibiting Abeta accumulation. A possible mechanistic basis for such a scenario is reviewed here.

Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Petanceska S, Browne P, Wassar D, Johnson-Traver S, Lochhead J, Ziolkowski C. · SunHealth Research Institute, USA. · Curr Alzheimer Res. · Pubmed #15974900 No free full text.

Abstract: Cholesterol-induced production of amyloid beta (Abeta) as a putative neurotoxin in Alzheimer's disease (AD), along with epidemiological evidence, suggests that statin drugs may provide benefit in treatment of the disorder. We tested the effect of once daily atorvastatin calcium (80 mg; two 40 mg tablets) on cognitive and/or behavioral decline in patients with mild-to-moderate AD. The study was designed as a pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to study medication employing last-observation-carried-forward (LOCF) ANCOVA as the primary statistical method of assessment. Alternate statistical methods were employed to further explore the effect of atorvastatin treatment on progression of deterioration. Of the 98 individuals with mild-to-moderate AD (Mini-Mental State Examination score of 12-28) providing Informed Consent, 71 were eligible for randomization, 67 were randomized and 63 completed the 3-month visit and were statistically evaluable. The primary outcome measures were change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) performance and the Clinical Global Impression of Change (CGIC). Secondary outcome measures included the MMSE, Geriatric Depression Scale (GDS), the Neuropsychiatric Inventory (NPI) and the ADCS Activities of Daily Living inventory (ADCS-ADL). Tertiary outcome measures included levels of total circulating cholesterol, LDL and VLDL, and circulating activity of the free radical scavenger enzymes superoxide dismutase (SOD) and glutathione peroxidase (GpX). Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared to placebo, but did not elicit a difference in circulating SOD or GpX activities. The observed beneficial clinical effect reached significance for the GDS (p = 0.040) and the ADAS-cog at 6 months (p = 0.003), was all but significant for the ADAS-cog (p = 0.055) at 12 months, and was of marginal significance for the CGIC (p = 0.073) and NPI (p = 0.071) at 12 months when employing the primary statistical approach (ANCOVA with LOCF). Application of repeated measures ANCOVA statistics revealed the difference was significant for the CGIC and marginally significant for the ADAS-cog, but not significant for the other clinical indices. This evaluation indicated significant time-by-treatment interactions (altered progression) for the ADAS-cog and MMSE, but not the CGIC. Application of random intercept regression analysis revealed a significant difference for the CGIC, ADAS-cog and MMSE. Regression analysis also indicated that atorvastatin produced change in the slope of deterioration on the MMSE. Accordingly, atorvastatin therapy may be an effective treatment and may slow the progression of AD among mild-to-moderately affected patients.

Cataldo AM, Petanceska S, Terio NB, Peterhoff CM, Durham R, Mercken M, Mehta PD, Buxbaum J, Haroutunian V, Nixon RA. · Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. · Neurobiol Aging. · Pubmed #15465622 No free full text.

Abstract: Early endosomes are a major site of amyloid precursor protein (APP) processing and a convergence point for molecules of pathologic relevance to Alzheimer's disease (AD). Neuronal endosome enlargement, reflecting altered endocytic function, is a disease-specific response that develops years before the earliest stage of AD and Down syndrome (DS). We examined how endocytic dysfunction is related to Abeta accumulation and distribution in early stage AD and DS. We found by ELISA and immunocytochemistry that the appearance of enlarged endosomes coincided with an initial rise in soluble Abeta40 and Abeta42 peptides, which preceded amyloid deposition. Double-immunofluorescence using numerous Abeta antibodies showed that intracellular Abeta localized principally to rab5-positive endosomes in neurons from AD brains and was prominent in enlarged endosomes. Abeta was not detectable in neurons from normal controls and was diminished after amyloid deposition in neuropathologically confirmed AD. These studies support growing evidence that endosomal pathology contributes significantly to Abeta overproduction and accumulation in sporadic AD and in AD associated with DS and may signify earlier disease-relevant disturbances of the signaling functions of endosomes.

Sparks DL, Friedland R, Petanceska S, Schreurs BG, Shi J, Perry G, Smith MA, Sharma A, Derosa S, Ziolkowski C, Stankovic G. · Roberts aboratory for NeurodegenerativeDisease Research, Sun Health Research Institute, Sun City, AZ, USA. · J Nutr Health Aging. · Pubmed #16886094 No free full text.

Abstract: Mounting evidence suggests copper may influence the progression of Alzheimer's disease by reducing clearance of the amyloid beta protein (Abeta) from the brain. Previous experiments show that addition of only 0.12 PPM copper (one-tenth the Environmental Protection Agency Human consumption limits) to distilled water was sufficient to precipitate the accumulation of Abeta in the brains of cholesterol-fed rabbits (1). Here we report that addition of copper to the drinking water of spontaneously hypercholesterolemic Watanabe rabbits, cholesterol-fed beagles and rabbits, PS1/APP transgenic mice produced significantly enhanced brain levels of Abeta. In contrast to the effects of copper, we found that aluminum- or zinc-ion-supplemented distilled water did not have a significant effect on brain Ab accumulation in cholesterol-fed rabbits. We also report that administration of distilled water produced a reduction in the expected accumulation of Ab in three separate animal models. Collectively, these data suggest that water quality may have a significant influence on disease progression and Ab neuropathology in AD.

Pacheco-Quinto J, Rodriguez de Turco EB, DeRosa S, Howard A, Cruz-Sanchez F, Sambamurti K, Refolo L, Petanceska S, Pappolla MA. · Neuroscience Center of Excellence, LSU Health Science Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA. · Neurobiol Dis. · Pubmed #16516482 No free full text.

Abstract: Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We tested the hypothesis that high serum homocysteine concentration may increase amyloid beta-peptide (Abeta) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBS(tm1Unc) mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis. The APP*/PS1*/CBS* mice showed significant elevations of serum homocysteine levels compared to the double transgenic APP*/PS1* model of amyloidosis. Results showed that female (but not male) APP*/PS1*/CBS* mice exhibited significant elevations of Abeta40 and Abeta42 levels in the brain. Correlations between homocysteine levels in serum and brain Abeta levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found. The causes of neuronal dysfunction and degeneration in AD are not fully understood, but increased production of Abeta seems to be of major importance. By unveiling a link between homocysteine and Abeta levels, these findings advance our understanding on the mechanisms involved in hyperhomocysteinemia as a risk factor for AD.

Sparks DL, Petanceska S, Sabbagh M, Connor D, Soares H, Adler C, Lopez J, Ziolkowski C, Lochhead J, Browne P. · Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ, USA. · Curr Alzheimer Res. · Pubmed #16375656 No free full text.

Abstract: Cholesterol clearly plays an influential role in promoting the production of amyloid beta (Abeta) and possibly the progression of Alzheimer's Disease (AD). The AD Cholesterol-Lowering Treatment trial (ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N = 32) compared to placebo (N = 31). We assessed the circulating levels of Abeta(1-40), Abeta(1-42), ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Abeta levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Abeta(1-40) occurred in low- compared to high-function controls, with a further significant increase in MCI compared to low-function controls. Circulating Abeta(1-40) levels were decreased in AD compared to MCI. Levels of Abeta(1-42) were not significantly different between the groups. The slight gradual increase in circulating Abeta(1-40) and Abeta(1-42) levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support a role for cholesterol in AD and a possible influence of increasing circulating copper levels. The deterioration of function in controls and transition to MCI may be associated with concomitant incremental increases in circulating Abeta(1-40) levels. Increased cholesterol and ceruloplasmin levels may be associated with slight deterioration in function among controls as a precursor to impairment considered MCI. The clinical benefit of atorvastatin therapy is clearly not associated with decreased circulating Abeta or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration.

Pedrini S, Carter TL, Prendergast G, Petanceska S, Ehrlich ME, Gandy S. · Farber Institute for Neurosciences, Thomas Jefferson University Philadelphia, Pennsylvania, USA. · PLoS Med. · Pubmed #15647781 links to  free full text

Abstract: BACKGROUND: Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, although the mechanisms underlying this apparent risk reduction are poorly understood. One popular hypothesis for statin action is related to the drugs' ability to activate alpha-secretase-type shedding of the alpha-secretase-cleaved soluble Alzheimer amyloid precursor protein ectodomain (sAPP(alpha)). Statins also inhibit the isoprenoid pathway, thereby modulating the activities of the Rho family of small GTPases-Rho A, B, and C-as well as the activities of Rac and cdc42. Rho proteins, in turn, exert many of their effects via Rho-associated protein kinases (ROCKs). Several cell-surface molecules are substrates for activated alpha-secretase-type ectodomain shedding, and regulation of shedding typically occurs via activation of protein kinase C or extracellular-signal-regulated protein kinases, or via inactivation of protein phosphatase 1 or 2A. However, the possibility that these enzymes play a role in statin-stimulated shedding has been excluded, leading us to investigate whether the Rho/ROCK1 protein phosphorylation pathway might be involved. METHODS AND FINDINGS: We found that both atorvastatin and simvastatin stimulated sAPP(alpha) shedding from a neuroblastoma cell line via a subcellular mechanism apparently located upstream of endocytosis. A farnesyl transferase inhibitor also increased sAPP(alpha) shedding, as did a dominant negative form of ROCK1. Most conclusively, a constitutively active ROCK1 molecule inhibited statin-stimulated sAPP(alpha) shedding. CONCLUSION: Together, these data suggest that statins exert their effects on shedding of sAPP(alpha) from cultured cells, at least in part, by modulation of the isoprenoid pathway and ROCK1.

Parvathy S, Ehrlich M, Pedrini S, Diaz N, Refolo L, Buxbaum JD, Bogush A, Petanceska S, Gandy S. · Farber Institute for Neurosciences of Thomas Jefferson University, Jefferson Hospital for Neuroscience, Philadelphia, Pennsylvania 19107, USA. · J Neurochem. · Pubmed #15287907 No free full text.

Abstract: Studies of metabolism of the Alzheimer amyloid precursor protein (APP) have focused much recent attention on the biology of juxta- and intra-membranous proteases. Release or 'shedding' of the large APP ectodomain can occur via one of two competing pathways, the alpha- and beta-secretase pathways, that are distinguished both by subcellular site of proteolysis and by site of cleavage within APP. The alpha-secretase pathway cleaves within the amyloidogenic Abeta domain of APP, precluding the formation of toxic amyloid aggregates. The relative utilization of the alpha- and beta-secretase pathways is controlled by the activation of certain protein phosphorylation signal transduction pathways including protein kinase C (PKC) and extracellular signal regulated protein kinase [ERK/mitogen-activated protein kinase (MAP kinase)], although the relevant substrates for phosphorylation remain obscure. Because of their apparent ability to decrease the risk for Alzheimer disease, the effects of statins (HMG CoA reductase inhibitors) on APP metabolism were studied. Statin treatment induced an APP processing phenocopy of PKC or ERK activation, raising the possibility that statin effects on APP processing might involve protein phosphorylation. In cultured neuroblastoma cells transfected with human Swedish mutant APP, atorvastatin stimulated the release of alpha-secretase-released, soluble APP (sAPPalpha). However, statin-induced stimulation of sAPPalpha release was not antagonized by inhibitors of either PKC or ERK, or by the co-expression of a dominant negative isoform of ERK (dnERK), indicating that PKC and ERK do not play key roles in mediating the effect of atorvastatin on sAPPalpha secretion. These results suggest that statins may regulate alpha-secretase activity either by altering the biophysical properties of plasma membranes or by modulating the function of as-yet unidentified protein kinases that respond to either cholesterol or to some intermediate in the cholesterol metabolic pathway. A 'phospho-proteomic' analysis of N2a cells with and without statin treatment was performed, revealing changes in the phosphorylation state of several protein kinases plausibly related to APP processing. A systematic evaluation of the possible role of these protein kinases in statin-regulated APP ectodomain shedding is underway.

Cataldo AM, Petanceska S, Peterhoff CM, Terio NB, Epstein CJ, Villar A, Carlson EJ, Staufenbiel M, Nixon RA. · Mailman Research Center, McLean Hospital, Belmont, Massachusetts 02478, USA. · J Neurosci. · Pubmed #12890772 links to  free full text

Abstract: Altered neuronal endocytosis is the earliest known pathology in sporadic Alzheimer's disease (AD) and Down syndrome (DS) brain and has been linked to increased Abeta production. Here, we show that a genetic model of DS (trisomy 21), the segmental trisomy 16 mouse Ts65Dn, develops enlarged neuronal early endosomes, increased immunoreactivity for markers of endosome fusion (rab5, early endosomal antigen 1, and rabaptin5), and endosome recycling (rab4) similar to those in AD and DS individuals. These abnormalities are most prominent in neurons of the basal forebrain, which later develop aging-related atrophy and degenerative changes, as in AD and DS. We also show that App, one of the triplicated genes in Ts65Dn mice and human DS, is critical to the development of these endocytic abnormalities. Selectively deleting one copy of App or a small portion of the chromosome 16 segment containing App from Ts65Dn mice eliminated the endosomal phenotype. Overexpressing App at high levels in mice did not alter early endosomes, implying that one or more additional genes on the triplicated segment of chromosome 16 are also required for the Ts65Dn endosomal phenotype. These results identify an essential role for App gene triplication in causing AD-related endosomal abnormalities and further establish the pathogenic significance of endosomal dysfunction in AD.

Chen F, Yang DS, Petanceska S, Yang A, Tandon A, Yu G, Rozmahel R, Ghiso J, Nishimura M, Zhang DM, Kawarai T, Levesque G, Mills J, Levesque L, Song YQ, Rogaeva E, Westaway D, Mount H, Gandy S, St George-Hyslop P, Fraser PE. · Centre for Research in Neurodegenerative Diseases, Departments of Laboratory Medicine and Pathobiology, Medical Biophysics and Medicine, University of Toronto, Ontario, Canada. · J Biol Chem. · Pubmed #10962005 links to  free full text

Abstract: Absence of functional presenilin 1 (PS1) protein leads to loss of gamma-secretase cleavage of the amyloid precursor protein (betaAPP), resulting in a dramatic reduction in amyloid beta peptide (Abeta) production and accumulation of alpha- or beta-secretase-cleaved COOH-terminal fragments of betaAPP (alpha- or beta-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as betaAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Abeta-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length betaAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of betaAPP to the Golgi compartment is necessary before alpha- and beta-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual gamma-secretase catalytic activity or in other functions indirectly related to gamma-secretase catalysis (e.g. an activator of gamma-secretase, a substrate adaptor for gamma-secretase, or delivery of gamma-secretase to betaAPP-containing compartments).