Gene Symbol: Mt3
Description: metallothionein 3
Alias: GIF, Mt-3, metallothionein-3, MT-III, growth inhibitory factor, metallothionein III
Species: rat

Top Publications

  1. You H, Oh D, Choi C, Lee D, Hahm K, Moon A, et al. Protective effect of metallothionein-III on DNA damage in response to reactive oxygen species. Biochim Biophys Acta. 2002;1573:33-8 pubmed
    ..These results strongly suggest that MT-III is involved in the protection of reactive oxygen species-induced DNA damage, probably via direct interaction with reactive oxygen species, and that MT-III acts as a neuroprotective agent. ..
  2. Tanji K, Irie Y, Uchida Y, Mori F, Satoh K, Mizushima Y, et al. Expression of metallothionein-III induced by hypoxia attenuates hypoxia-induced cell death in vitro. Brain Res. 2003;976:125-9 pubmed
  3. Pang L, Ru B. Studies on the epitope of neuronal growth inhibitory factor (GIF) with using of the specific antibody. J Biochem Mol Biol. 2005;38:646-9 pubmed
    Human neuronal growth inhibitory factor (GIF), a metalloprotein classified as metallothionein-3, is specifically expressed in mammal central nervous system (CNS)...
  4. Scudiero R, Cigliano L, Verderame M. Age-related changes of metallothionein 1/2 and metallothionein 3 expression in rat brain. C R Biol. 2017;340:13-17 pubmed publisher
    ..Expression of the ubiquitous MTs (1 and 2) and the brain specific MT3 have been studied in many neurodegenerative disorders...
  5. Kim H, Hwang Y, Jeong H. Metallothionein-III induces HIF-1alpha-mediated VEGF expression in brain endothelial cells. Biochem Biophys Res Commun. 2008;369:666-71 pubmed publisher
    ..These results suggest that MT-III upregulates VEGF production in brain endothelial cells by a HIF-1alpha-dependent mechanism. ..
  6. Somji S, Garrett S, Sens M, Gurel V, Sens D. Expression of metallothionein isoform 3 (MT-3) determines the choice between apoptotic or necrotic cell death in Cd+2-exposed human proximal tubule cells. Toxicol Sci. 2004;80:358-66 pubmed
    ..The present study provides evidence that MT-3 could play a role in controlling the choice between apoptosis and necrosis in multiple epithelial cell types of the human kidney. ..
  7. Ishigaki S, Niwa J, Ando Y, Yoshihara T, Sawada K, Doyu M, et al. Differentially expressed genes in sporadic amyotrophic lateral sclerosis spinal cords--screening by molecular indexing and subsequent cDNA microarray analysis. FEBS Lett. 2002;531:354-8 pubmed
    ..These results indicated that genes associated with the ubiquitin-proteasome system, oxidative toxicity, transcription, neuronal differentiation and inflammation might be involved in the pathogenesis of SALS. ..
  8. Tokuda E, Ono S, Ishige K, Naganuma A, Ito Y, Suzuki T. Metallothionein proteins expression, copper and zinc concentrations, and lipid peroxidation level in a rodent model for amyotrophic lateral sclerosis. Toxicology. 2007;229:33-41 pubmed
  9. Inuzuka T, Hozumi I, Tamura A, Hiraiwa M, Tsuji S. Patterns of growth inhibitory factor (GIF) and glial fibrillary acidic protein relative level changes differ following left middle cerebral artery occlusion in rats. Brain Res. 1996;709:151-31 pubmed
    b>Growth inhibitory factor (GIF) has been identified as a new metallothionein-like protein, the level of which is decreased in the Alzheimer's disease brain...

More Information


  1. Wang H, Li H, Cai B, Huang Z, Sun H. The effect of nitric oxide on metal release from metallothionein-3: gradual unfolding of the protein. J Biol Inorg Chem. 2008;13:411-9 pubmed
    Metallothionein-3 (MT-3), or neuronal growth inhibitory factor, which exhibits growth inhibitory activity, is a brain-specific metallothionein...
  2. Garrett S, Sens M, Todd J, Somji S, Sens D. Expression of MT-3 protein in the human kidney. Toxicol Lett. 1999;105:207-14 pubmed
    ..The finding that MT-3 is constitutively expressed in several glomerular and tubular epithelial elements of the human kidney warrants consideration of an expanded role for this protein family in maintaining renal homeostasis. ..
  3. Yamashita M, Glasgow E, Zhang B, Kusano K, Gainer H. Identification of cell-specific messenger ribonucleic acids in oxytocinergic and vasopressinergic magnocellular neurons in rat supraoptic nucleus by single-cell differential hybridization. Endocrinology. 2002;143:4464-76 pubmed
    ..These were identified as paternally expressed gene (Peg)5/neuronatin, metallothionein III, Peg3, synaptotagmin V, and a 3'-phosphoadenosine 5'-phosphosulfate synthase 2-related mRNA...
  4. Miyazaki I, Asanuma M, Higashi Y, Sogawa C, Tanaka K, Ogawa N. Age-related changes in expression of metallothionein-III in rat brain. Neurosci Res. 2002;43:323-33 pubmed
    Metallothionein (MT)-III is a metal binding protein, called growth inhibitory factor, and is mainly expressed in the central nervous system...
  5. Zhou B, Yang W, Ji J, Ru B. Differential display proteome analysis of PC-12 cells transiently transfected with metallothionein-3 gene. J Proteome Res. 2004;3:126-31 pubmed
    Metallothionein-3 (MT-3), also known as growth inhibitory factor, possesses several unique properties other than the common features of metallothionein family...
  6. Yeiser E, Fitch C, Horning M, Rutkoski N, Levenson C. Regulation of metallothionein-3 mRNA by thyroid hormone in developing rat brain and primary cultures of rat astrocytes and neurons. Brain Res Dev Brain Res. 1999;115:195-200 pubmed
    ..Unlike other members of this family, MT-3 has been shown to act as a neuronal growth inhibitory factor. MT-3 mRNA abundance increases throughout the developmental period, reaching adult levels by postnatal ..
  7. Watabe K, Hayashi Y, Kawazoe Y. Peripheral nerve avulsion injuries as experimental models for adult motoneuron degeneration. Neuropathology. 2005;25:371-80 pubmed
    ..factor (GDNF), brain-derived neurotrophic factor (BDNF), transforming growth factor-beta2 (TGFbeta2), and growth inhibitory factor (GIF) were injected into the facial canal...
  8. Pountney D, Dickson T, Power J, Vickers J, West A, Gai W. Association of metallothionein-III with oligodendroglial cytoplasmic inclusions in multiple system atrophy. Neurotox Res. 2011;19:115-22 pubmed publisher
    ..These results show that MT-III, but not MT-I/II, is a specific component of GCIs, present in abnormal aggregated forms external to the alpha-synuclein filaments. ..
  9. Romero Isart N, Jensen L, Zerbe O, Winge D, Vasak M. Engineering of metallothionein-3 neuroinhibitory activity into the inactive isoform metallothionein-1. J Biol Chem. 2002;277:37023-8 pubmed
    ..The functional significance of such heterogeneous cluster ensemble is discussed. ..
  10. Wang B, Wood I, Trayhurn P. PCR arrays identify metallothionein-3 as a highly hypoxia-inducible gene in human adipocytes. Biochem Biophys Res Commun. 2008;368:88-93 pubmed publisher
    ..MT-3 is a highly hypoxia-inducible gene in human adipocytes; the protein may protect adipocytes from hypoxic damage. ..
  11. Erickson J, Sewell A, Jensen L, Winge D, Palmiter R. Enhanced neurotrophic activity in Alzheimer's disease cortex is not associated with down-regulation of metallothionein-III (GIF). Brain Res. 1994;649:297-304 pubmed
    ..studies indicated that this enhanced neurotrophic activity of AD brain was due to a reduction of a growth inhibitory factor (GIF) that was subsequently shown to be a new member of the metallothionein (MT) gene family, and ..
  12. Ding Z, Teng X, Cai B, Wang H, Zheng Q, Wang Y, et al. Mutation at Glu23 eliminates the neuron growth inhibitory activity of human metallothionein-3. Biochem Biophys Res Commun. 2006;349:674-82 pubmed
    Human metallothionein-3 (hMT3), first isolated and identified as a neuronal growth inhibitory factor (GIF), is a metalloprotein expressed predominantly in brain...
  13. Hozumi I, Suzuki J, Kanazawa H, Hara A, Saio M, Inuzuka T, et al. Metallothionein-3 is expressed in the brain and various peripheral organs of the rat. Neurosci Lett. 2008;438:54-8 pubmed publisher
    Metallothionein-3 (MT-3), also known as growth inhibitory factor (GIF), was originally identified in the brain...
  14. Karotki A, Vasak M. Reaction of human metallothionein-3 with cisplatin and transplatin. J Biol Inorg Chem. 2009;14:1129-38 pubmed publisher
    ..The biological consequences of a substantially higher reactivity of cisplatin toward Zn7MT-3 than Zn7MT-2 in the acquired resistance to platinum-based drugs are discussed. ..
  15. Hozumi I, Uchida Y, Watabe K, Sakamoto T, Inuzuka T. Growth inhibitory factor (GIF) can protect from brain damage due to stab wounds in rat brain. Neurosci Lett. 2006;395:220-3 pubmed
    We examined the effect of growth inhibitory factor (GIF), also called metallothionein-III (MT-III), in brain damage using a stab wound model...
  16. Byun H, Kim D, Koh J. Obesity and downregulated hypothalamic leptin receptors in male metallothionein-3-null mice. Neurobiol Dis. 2011;44:125-32 pubmed publisher
    In the present study, we examined whether metallothionein-3 (Mt3), a zinc-binding protein that is specifically enriched in a brain, plays a role in obesity and hypothalamic leptin signaling in mice...
  17. Mocchegiani E, Giacconi R, Fattoretti P, Casoli T, Cipriano C, Muti E, et al. Metallothionein isoforms (I+II and III) and interleukin-6 in the hippocampus of old rats: may their concomitant increments lead to neurodegeneration?. Brain Res Bull. 2004;63:133-42 pubmed
    ..As a consequence, compensatory phenomena between MT isoforms may not occur in the old hippocampus due to chronic stress-like condition elicited by high persistent levels of interleukin-6. ..
  18. Hwang Y, Kim H, Han E, Jeong H. Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner. Toxicol Appl Pharmacol. 2008;231:318-27 pubmed publisher
    ..Taken together, these results suggest that the PI3K and ERK/Nrf2 signaling pathway controls the intracellular levels of ROS by regulating the expression of the antioxidant enzyme HO-1. ..
  19. Lanza C, Morando S, Voci A, Canesi L, Principato M, Serpero L, et al. Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. J Neurochem. 2009;110:1674-84 pubmed publisher
    ..These results support an antioxidant and neuroprotective activity for MSCs that was also confirmed in vitro on neuroblastoma cells exposed to an oxidative insult. ..
  20. Somji S, Garrett S, Sens M, Sens D. The unique N-terminal sequence of metallothionein-3 is required to regulate the choice between apoptotic or necrotic cell death of human proximal tubule cells exposed to Cd+2. Toxicol Sci. 2006;90:369-76 pubmed
    ..This is the identical sequence that has been shown to be responsible for the growth inhibitory activity of MT-3 in the neural system. ..
  21. Kim D, Kim E, Kim C, Sun W, Kim H, Uhm C, et al. Differential regulation of metallothionein-I, II, and III mRNA expression in the rat brain following kainic acid treatment. Neuroreport. 2003;14:679-82 pubmed
    ..Differential regulation of MT isoforms in neuron and gila suggests that each isoform might have distinct role in the cell-type dependent cellular responses against KA-evoked neural injuries. ..
  22. Tsuruma K, Shimazaki H, Ohno Y, Inoue Y, Honda A, Imai S, et al. Metallothionein-III deficiency exacerbates light-induced retinal degeneration. Invest Ophthalmol Vis Sci. 2012;53:7896-903 pubmed publisher
    ..We investigated the functional role of MT-III in light-induced retinal damage...
  23. Sakamoto T, Kawazoe Y, Uchida Y, Hozumi I, Inuzuka T, Watabe K. Growth inhibitory factor prevents degeneration of injured adult rat motoneurons. Neuroreport. 2003;14:2147-51 pubmed
    We examined neuroprotective effects of growth inhibitory factor (GIF) on injured adult rat facial motoneurons...
  24. Meloni G, Vasak M. Redox activity of ?-synuclein-Cu is silenced by Zn?-metallothionein-3. Free Radic Biol Med. 2011;50:1471-9 pubmed publisher
    ..These studies provide new insights into the bioinorganic chemistry of PD. ..
  25. Honda A, Komuro H, Hasegawa T, Seko Y, Shimada A, Nagase H, et al. Resistance of metallothionein-III null mice to cadmium-induced acute hepatotoxicity. J Toxicol Sci. 2010;35:209-15 pubmed
    ..In the present study, it was clearly found that MT-III null mice were resistant to Cd hepatotoxicity, although MT-I/II null mice were sensitive to its toxicity. MT-III may be an accelerative factor in Cd-induced acute hepatotoxicity. ..
  26. Martin B, Tokheim A, McCarthy P, Doms B, Davis A, Armitage I. Metallothionein-3 and neuronal nitric oxide synthase levels in brains from the Tg2576 mouse model of Alzheimer's disease. Mol Cell Biochem. 2006;283:129-37 pubmed
    Using antiserum against the recombinant isoform 3 of mouse brain metallothionein (MT3), the amount of MT3 protein was determined in whole brain homogenates from the Tg2576 transgenic mouse model of Alzheimer's Disease...
  27. Koumura A, Kakefuda K, Honda A, Ito Y, Tsuruma K, Shimazawa M, et al. Metallothionein-3 deficient mice exhibit abnormalities of psychological behaviors. Neurosci Lett. 2009;467:11-4 pubmed publisher
    Metallothioneins (MTs) are metal binding proteins and have four isoforms. MT-3, known as growth inhibitory factor (GIF), exists mainly in the central nervous system...
  28. Chapman G, Kay J, Kille P. Structural and functional analysis of the rat metallothionein III genomic locus. Biochim Biophys Acta. 1999;1445:321-9 pubmed
    b>Metallothionein III (MT III) has been reported to suppress neuronal growth in a rat in vitro model system...
  29. Lanza C, Raimondo S, Vergani L, Catena N, Sénès F, Tos P, et al. Expression of antioxidant molecules after peripheral nerve injury and regeneration. J Neurosci Res. 2012;90:842-8 pubmed publisher
    ..Taken together, these findings indicate that antioxidant molecules are differentially modulated and might, therefore, play an important role in peripheral nerve injury and regeneration. ..
  30. Puttaparthi K, Gitomer W, Krishnan U, Son M, Rajendran B, Elliott J. Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins. J Neurosci. 2002;22:8790-6 pubmed
  31. Yamada M, Hayashi S, Hozumi I, Inuzuka T, Tsuji S, Takahashi H. Subcellular localization of growth inhibitory factor in rat brain: light and electron microscopic immunohistochemical studies. Brain Res. 1996;735:257-64 pubmed
    The subcellular localization of growth inhibitory factor (GIF), a brain-specific member of the metallothionein family, was determined in the rat brain by electron microscopic immunohistochemistry using a rabbit antiserum against a ..
  32. Tougu V, Karafin A, Zovo K, Chung R, Howells C, West A, et al. Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-beta (1-42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators. J Neurochem. 2009;110:1784-95 pubmed publisher
    ..The molecular background underlying metal-chelating therapies for Alzheimer's disease is discussed in this light. ..
  33. Carrasco J, Giralt M, Molinero A, Penkowa M, Moos T, Hidalgo J. Metallothionein (MT)-III: generation of polyclonal antibodies, comparison with MT-I+II in the freeze lesioned rat brain and in a bioassay with astrocytes, and analysis of Alzheimer's disease brains. J Neurotrauma. 1999;16:1115-29 pubmed
    ..First identified as a growth inhibitory factor (GIF) of rat cortical neurons in vitro, it has subsequently been shown to be a member of the ..
  34. Gomi F, Nakano S, Uchida Y. Tolerance of aged rat brains to mild hyperoxia: possible involvement of higher GIF content. Brain Res. 2005;1033:113-6 pubmed
    ..The higher growth inhibitory factor (GIF) content in aged rat brains may be utilized as an antioxidant during hyperoxia.
  35. Acarin L, Carrasco J, Gonzalez B, Hidalgo J, Castellano B. Expression of growth inhibitory factor (metallothionein-III) mRNA and protein following excitotoxic immature brain injury. J Neuropathol Exp Neurol. 1999;58:389-97 pubmed
    ..The growth inhibitory factor (GIF), a member of the metallothionein family of proteins named metallothionein-III (MT-III), has been ..
  36. Uchida Y, Gomi F, Masumizu T, Miura Y. Growth inhibitory factor prevents neurite extension and the death of cortical neurons caused by high oxygen exposure through hydroxyl radical scavenging. J Biol Chem. 2002;277:32353-9 pubmed
    b>Growth inhibitory factor (GIF), a brain-specific member of the metallothionein family (MT-III), has been characterized as a inhibitory substance for neurotrophic factors in Alzheimer's disease brains...
  37. Tian T, Ni H, Sun B. Neurobehavioral Deficits in a Rat Model of Recurrent Neonatal Seizures Are Prevented by a Ketogenic Diet and Correlate with Hippocampal Zinc/Lipid Transporter Signals. Biol Trace Elem Res. 2015;167:251-8 pubmed publisher
    ..Then hippocampal mossy fiber sprouting and the protein levels of ZnT3, MT3, ApoE, CLU, and ACAT-1 were detected by Timm staining and Western blot analysis, respectively...
  38. Hozumi I, Inuzuka T, Ishiguro H, Hiraiwa M, Uchida Y, Tsuji S. Immunoreactivity of growth inhibitory factor in normal rat brain and after stab wounds--an immunocytochemical study using confocal laser scan microscope. Brain Res. 1996;741:197-204 pubmed
    The growth inhibitor factor (GIF) is a new member of the metallothionein family that is downregulated in Alzheimer's disease brain...
  39. Masters B, Quaife C, Erickson J, Kelly E, Froelick G, Zambrowicz B, et al. Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles. J Neurosci. 1994;14:5844-57 pubmed
    ..These results are discussed in light of the possibility that MT-III may participate in the utilization of zinc as a neuromodulator. ..
  40. Tsuji S, Kobayashi H, Uchida Y, Ihara Y, Miyatake T. Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease. EMBO J. 1992;11:4843-50 pubmed
    In previous studies, we discovered a growth inhibitory factor (GIF) that was abundant in normal human brain, but greatly reduced in Alzheimer's disease (AD) brain...
  41. Peng D, Hu T, Jiang A, Washington M, Moskaluk C, Schneider Stock R, et al. Location-specific epigenetic regulation of the metallothionein 3 gene in esophageal adenocarcinomas. PLoS ONE. 2011;6:e22009 pubmed publisher
    b>Metallothionein 3 (MT3) maintains intracellular metal homeostasis and protects against reactive oxygen species (ROS)-induced DNA damage...
  42. Ding Z, Zheng Q, Cai B, Yu W, Teng X, Wang Y, et al. Effect of alpha-domain substitution on the structure, property and function of human neuronal growth inhibitory factor. J Biol Inorg Chem. 2007;12:1173-9 pubmed
    Human metallothionein-3 (hMT3), also named human neuronal growth inhibitory factor (hGIF), is attractive due to its distinct neuronal growth inhibitory activity, which is not shown by other human MT isoforms...
  43. Chung R, Vickers J, Chuah M, Eckhardt B, West A. Metallothionein-III inhibits initial neurite formation in developing neurons as well as postinjury, regenerative neurite sprouting. Exp Neurol. 2002;178:1-12 pubmed
    ..Based on these results, we propose that MT-III, in the presence of brain extract, is a potent inhibitor of neurite sprouting, and may be involved in abnormal sprouting potentially underlying both AD and epilepsy. ..
  44. Amoureux M, Wurch T, Pauwels P. Modulation of metallothionein-III mRNA content and growth rate of rat C6-glial cells by transfection with human 5-HT1D receptor genes. Biochem Biophys Res Commun. 1995;214:639-45 pubmed
    ..The inverse proportion between mitogenic activity and MT-III mRNA content suggests that MT-III may act as a growth inhibitory factor in rat C6-glial cells.
  45. Kobayashi H, Uchida Y, Ihara Y, Nakajima K, Kohsaka S, Miyatake T, et al. Molecular cloning of rat growth inhibitory factor cDNA and the expression in the central nervous system. Brain Res Mol Brain Res. 1993;19:188-94 pubmed
    Human growth inhibitory factor (GIF) is a new metallothionein-related molecule whose expression is markedly reduced in Alzheimer's disease (AD) brain...
  46. Ma F, Wang H, Chen B, Wang F, Xu H. Metallothionein 3 attenuated the apoptosis of neurons in the CA1 region of the hippocampus in the senescence-accelerated mouse/PRONE8 (SAMP8). Arq Neuropsiquiatr. 2011;69:105-11 pubmed
    b>Metallothionein 3 (MT-3) has been shown to protect against apoptotic neuronal death in the brains of patients with Alzheimer's disease. Zinc is a potent inhibitor of caspase-3 and its deficiency was found to promote apoptosis...
  47. Lee S, Park M, Kim H, Koh J. Metallothionein-3 regulates lysosomal function in cultured astrocytes under both normal and oxidative conditions. Glia. 2010;58:1186-96 pubmed publisher
    ..Here, using astrocytes lacking metallothionein-3 (MT3), a potential source of labile zinc in the brain, we studied the role of MT3 in oxidative stress responses...
  48. Yanagitani S, Miyazaki H, Nakahashi Y, Kuno K, Ueno Y, Matsushita M, et al. Ischemia induces metallothionein III expression in neurons of rat brain. Life Sci. 1999;64:707-15 pubmed
    b>Metallothionein III (MT-III) is a brain-specific member of the metallothionein family and binds zinc in vivo...
  49. Koumura A, Hamanaka J, Shimazawa M, Honda A, Tsuruma K, Uchida Y, et al. Metallothionein-III knockout mice aggravates the neuronal damage after transient focal cerebral ischemia. Brain Res. 2009;1292:148-54 pubmed publisher
  50. Choi K, Elashoff M, Higgs B, Song J, Kim S, Sabunciyan S, et al. Putative psychosis genes in the prefrontal cortex: combined analysis of gene expression microarrays. BMC Psychiatry. 2008;8:87 pubmed publisher
    ..PCR, we validated a set of genes such as up-regulated metallothioneins (MT1E, MT1F, MT1H, MT1K, MT1X, MT2A and MT3) and down-regulated neuropeptides (SST, TAC1 and NPY) in the dorsolateral prefrontal cortex of psychosis patients...
  51. Williams B, Yaddanapudi K, Kirk C, Soman A, Hornig M, Lipkin W. Metallothioneins and zinc dysregulation contribute to neurodevelopmental damage in a model of perinatal viral infection. Brain Pathol. 2006;16:1-14 pubmed
    ..Abnormal zinc metabolism and mechanisms of neuroplasticity may contribute to the pathogenesis of disease in this model, raising more general implications for neurodevelopmental damage following viral infections in early life. ..
  52. He J, Huang C, Jiang J, Lv L. Propofol exerts hippocampal neuron protective effects via up-regulation of metallothionein-3. Neurol Sci. 2013;34:165-71 pubmed publisher
    ..Recent years emerging evidence has demonstrated that metallothionein-3 (MT-3), a growth inhibitory factor that exists mainly in the central nervous system, exhibited neuroprotective effect in vivo...
  53. Ni H, Ren S, Zhang L, Sun Q, Tian T, Feng X. Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus. Toxicol Lett. 2013;217:162-9 pubmed publisher
  54. Cai B, Zheng Q, Teng X, Chen D, Wang Y, Wang K, et al. The role of Thr5 in human neuron growth inhibitory factor. J Biol Inorg Chem. 2006;11:476-82 pubmed
    GIF, a member of the metallothionein (MT) family (assigned as MT3), is a neuron growth inhibitory factor that inhibits neuron outgrowth in Alzheimer's disease...