Alzheimer Disease: Arancio O

Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD. · Department of Neurology and Neurosurgery,North Shore-LIJ Health System, NY, USA. · Curr Mol Med. · Pubmed #18331231 No free full text.

Abstract: This review focuses on the current findings regarding interaction between amyloid beta peptide (Abeta) and receptor for advanced glycation endproducts (RAGE) and its roles in the pathogenesis of Alzheimer's disease (AD). As a ubiquitously expressed cell surface receptor, RAGE mediates the effects of Abeta on microglia, blood-brain barrier (BBB) and neurons through activating different signaling pathways. Data from autopsy brain tissues, in vitro cell cultures and transgenic mouse models suggest that Abeta-RAGE interaction exaggerates neuronal stress, accumulation of Abeta, impaired learning memory, and neuroinflammation. Blockade of RAGE protects against Abeta-mediated cellular perturbation. These findings may have an important therapeutic implication for neurodegenerative disorders relevant to AD.

Puzzo D, Palmeri A, Arancio O. · Department of Pathology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. · Rev Neurosci. · Pubmed #17180876 No free full text.

Abstract: Amyloid-beta (Abeta), a peptide thought to play a crucial role in Alzheimer's disease (AD), has attracted scientific interest with the aim of characterizing the mechanisms by which it is involved in AD pathogenesis. Abeta has been found to markedly impair hippocampal long-term potentiation (LTP), a widely studied cellular model of synaptic plasticity that is thought to underlie learning and memory. The overall purpose of this review is to define the role of the nitric oxide (NO)/cGMP/cAMP-regulatory element binding (CREB) pathway in beta-amyloid-induced changes of basal neurotransmission and synaptic plasticity in the hippocampus, a structure within the temporal lobe of the brain critical for memory storage.

Sant'Angelo A, Trinchese F, Arancio O. · Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA. · Neurochem Res. · Pubmed #12737525 No free full text.

Abstract: Over the past several years researchers have engineered many transgenic models of Alzheimer's disease. Since loss of memory is one of the major hallmarks of the disorder, the phenotypic characterization of these animals has included both behavioral tests which aim to evaluate learning abilities, and electrophysiological studies to analyze synaptic transmission and long-term potentiation, a widely studied cellular model of learning and memory. These studies are fundamental for the design of novel therapies for the treatment and/or prevention of Alzheimer's disease.

Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. · Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA. · Nat Med. · Pubmed #18806802 No free full text.

Abstract: Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-beta protein (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Abeta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.

Trinchese F, Fa' M, Liu S, Zhang H, Hidalgo A, Schmidt SD, Yamaguchi H, Yoshii N, Mathews PM, Nixon RA, Arancio O. · Department of Pathology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA. · J Clin Invest. · Pubmed #18596919 links to  free full text

Abstract: Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD.

Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH, Arancio O, Duff K. · Department of Pathology, Taub Institute for Research on Alzheimer's Disease, Columbia University, Black Building #5-513, 650 West 168th Street, New York, NY 10032, USA. · Neurobiol Dis. · Pubmed #18504134 No free full text.

Abstract: In the last decade, multiple lines of transgenic APP overexpressing mice have been created that recapitulate certain aspects of Alzheimer's disease (AD). However, none of the previously reported transgenic APP overexpressing rat models developed AD-like beta-amyloid (Abeta) deposits, or age-related learning and memory deficits. In the present study, we have characterized a transgenic rat model overexpressing transgenes with three, familial AD mutations (two in APP and one in PS1) that were developed by Flood et al. [Flood, D.G., et al., Abeta deposition in a transgenic rat model of Alzheimer's disease. Society for Neuroscience 2003, Washington, DC, 2003]. From the age of 9 months, these rats develop Abeta deposits in both diffuse and compact forms, with the latter being closely associated with activated microglia and reactive astrocytes. Impaired long-term potentiation (LTP) was revealed by electrophysiological recordings performed on hippocampal slices from rats at 7 months of age, which is 2 months before the appearance of amyloid plaques. The deficit in LTP was accompanied by impaired spatial learning and memory in the Morris water maze, which became more pronounced in transgenic rats of 13 months of age. For Tg rats of both ages, there was a trend for cognitive impairment to correlate with total Abeta42 levels in the hippocampus. The rat model therefore recapitulates AD-like amyloid pathology and cognitive impairment. The advantage of the rat model over the available mouse models is that rats provide better opportunities for advanced studies, such as serial CSF sampling, electrophysiology, neuroimaging, cell-based transplant manipulations, and complex behavioral testing.

Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, Herman M, Ho L, Kreber R, Honig LS, Ganetzky B, Duff K, Arancio O, Small SA. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. · Proc Natl Acad Sci U S A. · Pubmed #18480253 links to  free full text

Abstract: Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.

Berman DE, Dall'Armi C, Voronov SV, McIntire LB, Zhang H, Moore AZ, Staniszewski A, Arancio O, Kim TW, Di Paolo G. · Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA. · Nat Neurosci. · Pubmed #18391946 links to  free full text

Abstract: Synaptic dysfunction caused by oligomeric assemblies of amyloid-beta peptide (Abeta) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric Abeta decreases the level of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), a phospholipid that regulates key aspects of neuronal function. The destabilizing effect of Abeta on PtdIns(4,5)P2 metabolism was Ca2+-dependent and was not observed in neurons that were derived from mice that are haploinsufficient for Synj1. This gene encodes synaptojanin 1, the main PtdIns(4,5)P2 phosphatase in the brain and at the synapses. We also found that the inhibitory effect of Abeta on hippocampal long-term potentiation was strongly suppressed in slices from Synj1+/- mice, suggesting that Abeta-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P2 balance in the brain.

Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li HF, Feng L, Lecanu L, Walker BR, Planel E, Arancio O, Gozes I, Aisen PS. · Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Road N.W., Washington, DC 20057, USA. · J Pharmacol Exp Ther. · Pubmed #18199809 links to  free full text

Abstract: Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.

Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O. · Department of Pathology and Taub Institute, Columbia University, New York, NY 10032, USA. · Cell. · Pubmed #16923396 No free full text.

Abstract: The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD). We now show that a component of the pathway, ubiquitin C-terminal hydrolase L1 (Uch-L1), is required for normal synaptic and cognitive function. Transduction of Uch-L1 protein fused to the transduction domain of HIV-transactivator protein (TAT) restores normal enzymatic activity and synaptic function both in hippocampal slices treated with oligomeric Abeta and in the APP/PS1 mouse model of AD. Moreover, intraperitoneal injections with the fusion protein improve the retention of contextual learning in APP/PS1 mice over time. The beneficial effect of the Uch-L1 fusion protein is associated with restoration of normal levels of the PKA-regulatory subunit IIalpha, PKA activity, and CREB phosphorylation.

Puzzo D, Arancio O. · Department of Pathology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA. · Curr Alzheimer Res. · Pubmed #16842092 No free full text.

Abstract: Synaptic dysfunction is involved in early stages of Alzheimer's disease (AD). Amyloid-beta peptides (Abeta), a neuropathologic hallmark of the disease, have been shown to alter synaptic function. Given that Abeta is present in different forms including monomeric, oligomeric and fibrillar species, we have investigated whether fibrillar Abeta impairs synaptic function. Here we report that a synthetic fibrillar form of Abeta impairs the late protein-synthesis dependent phase of LTP without affecting the early protein-synthesis independent phase. These findings add to previous reports that Abeta oligomers are highly toxic to cells and might cause synaptic dysfunction, and suggest that a therapeutic intervention in AD should include the use of drugs inhibiting and disassembling fibril formation in addition to drugs inhibiting oligomers formation.

Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O. · Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA. · J Neurosci. · Pubmed #16033898 links to  free full text

Abstract: Amyloid-beta (Abeta), a peptide thought to play a crucial role in Alzheimer's disease (AD), has many targets that, in turn, activate different second-messenger cascades. Interestingly, Abeta has been found to markedly impair hippocampal long-term potentiation (LTP). To identify a new pathway that might be responsible for such impairment, we analyzed the role of the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK)/cAMP-responsive element-binding protein (CREB) cascade because of its involvement in LTP. The use of the NO donor 2-(N,N-dethylamino)-diazenolate-2-oxide diethylammonium salt (DEA/NO), the sGC stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine, or the cGMP-analogs 8-bromo-cGMP and 8-(4-chlorophenylthio)-cGMP reversed the Abeta-induced impairment of CA1-LTP through cGK activation. Furthermore, these compounds reestablished the enhancement of CREB phosphorylation occurring during LTP in slices exposed to Abeta. We also found that Abeta blocks the increase in cGMP immunoreactivity occurring immediately after LTP and that DEA/NO counteracts the effect of Abeta. These results strongly suggest that, when modulating hippocampal synaptic plasticity, Abeta downregulates the NO/cGMP/cGK/CREB pathway; thus, enhancement of the NO/cGMP signaling may provide a novel approach to the treatment of AD and other neurodegenerative diseases with elevated production of Abeta.

Zhang H, Gong B, Liu S, Fa' M, Ninan I, Staniszewski A, Arancio O. · Department of Pathology and The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA. · Curr Alzheimer Res. · Pubmed #15974910 No free full text.

Abstract: To search for potential mechanism that might alter synaptic transmission following Abeta increase we have examined the presynaptic component of transmitter release. As parameters of synaptic transmission that might underlie presynaptic mechanisms, we have used paired-pulse facilitation (PPF), post-tetanic potentiation (PTP), and synaptic fatigue (SF) at the connection between the hippocampal Schaffer-collateral pathway and CA1 pyramidal neurons in approximately 5 month old double transgenic mice overexpressing the mutated form of amyloid precursor protein (APPK670N, M671L) and presenilin 1 (PS1M146V). While the presynaptic mechanisms of PPF and PTP were not compromised in the APP/PS1 mice, SF was more pronounced in the double transgenic animals. The percentage of the 40th fEPSP slope over the first during the tetanus was 18 -/+ 3% in APP/PS1 vs. 26 -/+ 2% in WT. Thus, it is likely that presynaptic mechanisms underlying SF but not PPF and PTP, may account for synaptic dysfunction in APP/PS1 mice.

Takuma K, Yao J, Huang J, Xu H, Chen X, Luddy J, Trillat AC, Stern DM, Arancio O, Yan SS. · Departments of Surgery, Pathology, and Neurology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. · FASEB J. · Pubmed #15665036 links to  free full text

Abstract: Amyloid-beta peptide (Abeta) binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, is a cofactor facilitating Abeta-induced cell stress. We hypothesized that ABAD provides a direct link between Abeta and cytotoxicity via mitochondrial oxidant stress. Neurons cultured from transgenic (Tg) mice with targeted overexpression of a mutant form of amyloid precursor protein and ABAD (Tg mAPP/ABAD) displayed spontaneous generation of hydrogen peroxide and superoxide anion, and decreased ATP, as well as subsequent release of cytochrome c from mitochondria and induction of caspase-3-like activity followed by DNA fragmentation and loss of cell viability. Generation of reactive oxygen species (ROS) was associated with dysfunction at the level of mitochondrial complex IV (cytochrome c oxidase, or COX). In neurons cultured from Tg mAPP/ABAD mice, COX activity was selectively decreased, and cyanide, an inhibitor of complex IV, exacerbated leakage of ROS, induction of caspase-3-like activity, and DNA fragmentation. In vivo, Tg mAPP/ABAD mice displayed reduced levels of brain ATP and COX activity, diminished glucose utilization, as well as electrophysiological abnormalities in hippocampal slices compared with Tg mAPP mice. In contrast, neither Tg ABAD mice nor nontransgenic (non-TG) littermates showed similar changes in ATP, COX activity, glucose utilization or electrophysiological properties. Each of the genotypes (Tg ABAD, Tg mAPP and Tg mAPP/ABAD mice, and non-TG littermates) displayed normal reproductive fitness, development and lifespan (1) These findings link ABAD-induced oxidant stress to critical aspects of Alzheimer's disease (AD)-associated cellular dysfunction, suggesting a pivotal role for this enzyme in the pathogenesis of AD.

Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O. · The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA. · J Clin Invest. · Pubmed #15578094 links to  free full text

Abstract: Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.

Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, Luddy JS, Lue LF, Walker DG, Roher A, Buttini M, Mucke L, Li W, Schmidt AM, Kindy M, Hyslop PA, Stern DM, Du Yan SS. · Department of Psychiatry, Physiology and Neuroscience, Dementia Research Center, Nathan Kline Institute, New York University School of Medicine, NY 10032, USA. · EMBO J. · Pubmed #15457210 links to  free full text

Abstract: Receptor for Advanced Glycation Endproducts (RAGE), a multiligand receptor in the immunoglobulin superfamily, functions as a signal-transducing cell surface acceptor for amyloid-beta peptide (Abeta). In view of increased neuronal expression of RAGE in Alzheimer's disease, a murine model was developed to assess the impact of RAGE in an Abeta-rich environment, employing transgenics (Tgs) with targeted neuronal overexpression of RAGE and mutant amyloid precursor protein (APP). Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities in spatial learning/memory, accompanied by altered activation of markers of synaptic plasticity and exaggerated neuropathologic findings, before such changes were found in mAPP mice. In contrast, Tg mice bearing a dominant-negative RAGE construct targeted to neurons crossed with mAPP animals displayed preservation of spatial learning/memory and diminished neuropathologic changes. These data indicate that RAGE is a cofactor for Abeta-induced neuronal perturbation in a model of Alzheimer's-type pathology, and suggest its potential as a therapeutic target to ameliorate cellular dysfunction.

Veeranna, Kaji T, Boland B, Odrljin T, Mohan P, Basavarajappa BS, Peterhoff C, Cataldo A, Rudnicki A, Amin N, Li BS, Pant HC, Hungund BL, Arancio O, Nixon RA. · Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA. · Am J Pathol. · Pubmed #15331404 links to  free full text

Abstract: Aberrant phosphorylation of the neuronal cytoskeleton is an early pathological event in Alzheimer's disease (AD), but the underlying mechanisms are unclear. Here, we demonstrate in the brains of AD patients that neurofilament hyperphosphorylation in neocortical pyramidal neurons is accompanied by activation of both Erk1,2 and calpain. Using immunochemistry, Western blot analysis, and kinase activity measurements, we show in primary hippocampal and cerebellar granule (CG) neurons that calcium influx activates calpain and Erk1,2 and increases neurofilament phosphorylation on carboxy terminal polypeptide sites known to be modulated by Erk1,2 and to be altered in AD. Blocking Erk1,2 activity either with antisense oligonucleotides to Erk1,2 mRNA sequences or by specifically inhibiting its upstream activating kinase MEK1,2 markedly reduced neurofilament phosphorylation. Calpeptin, a cell-permeable calpain inhibitor, blocked both Erk1,2 activation and neurofilament hyperphosphorylation at concentrations that inhibit calpain-mediated cleavage of brain spectrin. By contrast, inhibiting Erk1,2 with U-0126, a specific inhibitor of Mek1,2, had no appreciable effect on ionomycin-induced calpain activation. These findings demonstrate that, under conditions of calcium injury in neurons, calpains are upstream activators of Erk1,2 signaling and are likely to mediate in part the hyperphosphorylation of neurofilaments and tau seen at early stages of AD as well as the neuron survival-related functions of the MAP kinase pathway.

Trinchese F, Liu S, Ninan I, Puzzo D, Jacob JP, Arancio O. · Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. · J Mol Neurosci. · Pubmed #15314245 No free full text.

Abstract: Approximately 2 million people in the United States suffer from Alzheimer's disease (AD), which is the most common cause of chronic dementia among the aging population. During the last 7 yr, excellent opportunities to screen drugs against AD have been provided by animal models of the disease. Because even in the fastest model, AD pathology does not start before the end of the second month, it has been necessary to wait at least until that age to inject drugs into the animal to assess whether they prevent, reduce, or revert synaptic impairment, plaque formation, and increase of beta-amyloid (Abeta) levels, the main features of the disease. A solution to the problems mentioned above is achieved by the present fast, efficient, and reproducible cultured cell system from animal models of AD or Abeta-associated diseases, for the screening and testing of compounds for the treatment and therapy of AD or Abeta-associated diseases.

Trinchese F, Liu S, Battaglia F, Walter S, Mathews PM, Arancio O. · Department of Psychiatry, New York University School of Medicine, New York, NY, USA. · Ann Neurol. · Pubmed #15174014 No free full text.

Abstract: Increasing evidence points to synaptic plasticity impairment as one of the first events in Alzheimer's disease (AD). However, studies on synaptic dysfunction in different transgenic AD models that overexpress familial AD mutant forms of amyloid precursor protein (APP) and/or presenilin (PS) have provided conflicting results. Both long-term potentiation (LTP) and basal synaptic transmission (BST) have been found to be both unchanged and altered in different models and under differing experimental conditions. Because of their more robust amyloid-beta (Abeta) deposition, double transgenic mice currently are used by several laboratories as an AD model. Here, we report that mice overexpressing APP (K670N:M671L) together with PS1 (M146L) have abnormal LTP as early as 3 months of age. Interestingly, reduced LTP paralleled plaque appearance and increased Abeta levels and abnormal short-term memory (working memory). BST and long-term memory (reference memory) are impaired only later (approximately 6 months) as amyloid burden increases. Abeta pathology across different ages did not correlate with synaptic and cognitive deficits, suggesting that Abeta levels are not a marker of memory decline. In contrast, progression of LTP impairment correlated with the deterioration of working memory, suggesting that percentage of potentiation might be an indicator of the cognitive decline and disease progression in the APP/PS1 mice.

Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H. · Center for Reproductive Sciences and Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. · Science. · Pubmed #15087549 links to  free full text

Abstract: Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD.

Battaglia F, Trinchese F, Liu S, Walter S, Nixon RA, Arancio O. · Department of Psychiatry, Nathan Kline Institute for Psychiatric Research, NYU School of Medicine, Orangeburg, NY 10962, USA. · J Mol Neurosci. · Pubmed #14501020 No free full text.

Abstract: Calpains modulate processes that govern the function and metabolism of proteins key to the pathogenesis of Alzheimer's disease, including tau and amyloid precursor protein. Because activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer's disease, we are currently testing the hypotheses that a treatment with calpain inhibitors might restore normal cognition and synaptic transmission in a transgenic model of Alzheimer's disease, the APP (K670N:M671L)/PS1(M146L) mouse. Findings derived from these studies will provide a novel approach to cognitive enhancement in Alzheimer's disease.

Di Rosa G, Odrijin T, Nixon RA, Arancio O. · Nathan Kline Institute, NYU School of Medicine, Orangeburg, NY 10962, USA. · J Mol Neurosci. · Pubmed #12212771 No free full text.

Abstract: Activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer's disease (AD) (Liu et al., 1999; Rapoport, 1999; Selkoe, 1994). Calpains regulate the function of many proteins by limited proteolysis and initiate the complete degradation of other proteins. In particular, they modulate processes that govern the function and metabolism of proteins key to the pathogenesis of AD, including tau and amyloid precursor protein (APP). (Xie and Johnson, 1998; Wang, 2000). We have found that overexpression of APP(K670M:N671L) and PS1(M146L) proteins in hippocampal cultures derived from transgenic mice causes an increase in the frequency of spontaneous release of neurotransmitter. We have also found that calpain immunoreactive clusters are co-localized with immunoreactivity for the vesicle-associated presynaptic marker, synaptophysin. Moreover, application of calpain inhibitor reduces the frequency of spontaneous release of neurotransmitter. Therefore, we have hypothesized that calpains might contribute to the increase in transmitter release. Based on this hypothesis, we propose to test whether it is possible to restore normal synaptic transmission between cells derived from the transgenic model of AD by using calpain inhibitors. The transgenic mouse model also shows spatial learning impairment, a phenomenon that is thought to be associated with plastic changes at synaptic level. Therefore, we will also test whether we can rescue the learning impairment through a treatment with calpain inhibitors.