Growth hormone/insulin-like growth factor 1 and Alzheimer s disease

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1 Chinese Bulletin of Life Sciences Vol. 19, No. 2 Apr., (2007) / 1 ( ) / -1(GH/IGF-1) (AD) (GH) (GHRH) GH/IGF-1 GH/IGF-1 (AD) GH/IGF-1 AD AD / 1 AD 1 R743 Q R592 Growth hormone/insulin-like growth factor 1 and Alzheimer s disease ZHANG Ting, SUN Manji* (Institute of Pharmacology and Toxicology, Beijing , China) Abstract: The synthesis, secretion, regulation and biological activity of the growth hormone (GH) / insulin-like growth factor- 1 (IGF-1) play important parts in the development of Alzheimer s disease (AD). The synthesis and secretion are regulated by the stimulants, the GH-releasing hormone (GHRH). Decrement of the activity of the somatotrophic axis causes a series of changes of physiological functions. The deficiency of GH/IGF-1 results in aging and decline of cognition. Supplementation of the related hormones will protect or reverse the cognitive deficits. The evidence available strongly indicates that GH / IGF-1 therapy in Alzheimer s dementia may be addressing pathogenic processes. The role of GH/IGF-1 in the development of Alzheimer s disease and pharmacological research are reviewed Key words: growth hormone; insulin-like growth factor 1; Alzheimer s disease 1 (growth hormone, GH) (GH-releasing hormone GHRH) GH, GH ( 1) GH 50 GH 60 GH GH GH GH (1) IGFs (somatomedin, SM) GH IGFs IGFs (2) (1964 ) (1931 ) * Tel: sunmj@nic.bmi.ac.cn

2 / GH GH IGF-1 GH GH 12 18h IGF-1 GH IGF-1 GH IGF-1 GH IGF-1 GH/IGF-1 GH DNA mrna IGF (Alzheimer s disease AD) (senile plaque, SP) (neurofibrillary tangles, NFT) AD AD β- (β-amyloid peptide, Aβ) ( SP ) NFT AD AD AD GH/IGF-1 AD 2 GH AD 2.1 AD GH AD (acetylcholine) (dopamine) ( somatostatin) ( noradrenaline) AD Gomez [1] AD (vascular dementia VD) AD VD GH GHRH AD VD AD GH (TSH) CT GHRH GH 28 AD 28 TSH (TRH) [2] Gilles [3] AD GH 1

3 210 (clonidine) GH SDAT(senile dementia of the Alzheimer type SDAT) GH SDAT GH Lesch [4] AD - - (HPS) - - (HPA),, AD GHRH GH GHRH (ACTH) GHRH GH IGF-1 GHRH GH ACTH GHRH AD (bromocriptine) GH (prolactin PRL) GH DAT(dementia of the Alzhei-mertype) MID (multi-infarct dementia, MID) [5] AD (pyridostigmine) GH GH [6] AD GH AD GH GH IGF % GH LDL-CHol GH (somatopause) [7] GH/IGF-1 DSST (the digit symbol substitution test) CST(the concept shifting task) IGF-1 DSST CST AD GH/IGF-1 [8] AD GH GH [9] GH AD GHRH Vitiello [10] GH [ AD MCI mild cognition impairment)] GH AD GH Aβ AD GH - AD [11] GH GH GH ( ) GH GH 2.2 AD GH GH GH GH, GHRH GH AD (ChEIs) GH GHRH Pirenzepine( M ) GHRH GH [12] GH

4 / GH AD GH AD IGF-1 GH AD GHRH GH (atropine) DAT GHRH GH AD GH [12-13] ChEIs GH (rivastigmine) ChEI, GHRH ( ) GH (donepezil, AD AD ) GH/IGF-1 GH GHRH GH 53% IGF-1 31% GH/IGF-1 [8] (physostigmine ) SS ( ) GHRH [14] GH GH 3 IGF-1 AD 3.1 AD IGF-1 IGF-1 IGF-1 AD Aβ tau IGF-1 AD IGF-1 IGF-2 IGF-1 IGF-1 IGF-1 [15] IGF-1 CNS DNA RNA AD IGF-1 AD [16] IGF-1 IGF-1 IGF IGF-1/IGF-2 IGF-2 [17] AD IGF-1 IGF-1 [18] TNF-α TNF AD MCI IGF-1 [19] Xing [20] IGF-1 Aβ IGF-1(10 100nmol/L) Aβ amylion IGF-1 Aβ IGF-1 tau (AD ) IGF-1 Aβ Aβ Aβ Tg 2576 IGF-1 Aβ [21-22] Carro Torres-Aleman [21] IGF-1 Aβ Aβ Aβ Aβ IGF-1 AD tau IGF-1 AD AD IGF-1 IGF-1 tau

5 212 IGF-1 AD [22] IGF-1-3 (glycogen synthase kinase 3, GSK-3) tau IGF-1 GSK-3 tau tau 2(insulin receptor substrate, IRS-2) IGF-1 IGF-1 IRS-2 IGF-1 tau IGF-1 tau IGF-1 [21-23] IGF-1 ( IGF-1 ) IGF-1 (insulin-like growth factor-1 binding proteins, IGFBPs) IGF-1 IGF-1 IGFBPs IGF-1 IGF-1 IGF-1 [24] IGF-1 IGF Aβ tau IGF-1 IGF IGF-1 AD GH IGF-1 GH, IGF-1, GH IGF-1 GH GH GH IGF-1 [25] APP/PS2 Aβ precursor protein (APP) presenilin (PS)-2 Aβ IGF-1 Aβ AD IGF-1 Aβ ( J ) Aβ Aβ IGF-1 APP IGF-1 AD [26] IGF-1 GH GH 1B [27] 4 GH / IGF-1 AD GH IGF-1 (GHD) (turner syndrome, TS) (intra uterirne growth retardation, IUGR) (central precocious puberty, CPP) (famillia short stature, FSS) GH GH ( imidazoline ) IGF-1 AD IGF-1 IGF-1 IGF-1 AD IGF-1 IGF-1 GHRH IGF-1 ( IGFBPs IGF-1) AD IGF-1 GH AD [1] Gomez I M, Aguilar M, Navarro M A, et al. GH response to GH-releasing hormone (GHRH) in Alzheimer and vascular dementia. Relation with somatostatin cerebrospinal levels. Ann Endocrinol (Paris), 1996, 57(2): [2] Gomez J M, Aguilar M, Soler J. Growth hormone and thyrotropin hormone secretion in Alzheimer's disease. J Nutr Health Aging, 2000, 4(4): [3] Gilles C, Ryckaert P, De Mol J, et al. Clonidine-induced growth hormone secretion in elderly patients with senile dementia of the Alzheimer type and major depressive disorder. Psychiatry Res, 1989, 27(3): [4] Lesch K P, Ihl R, Frolich L. Endocrine responses to growth hormone releasing hormone and corticotropin releasing hormone in early-onset Alzheimer's disease. Psychiatry Res, 1990, 33(2): [5] Higashi S, Fujita M, Nishimoto Y, et al. Neuroendocrine studies in dementia patients: responses of plasma GH and PRL following bromocriptine administration. Acta Neurol Scand, 1994, 90(1): [6] van Amelsvoort T, Murphy D G, Robertson D, et al. Effects of long-term estrogen replacement therapy on growth hormone response to pyridostigmine in healthy postmeno-

6 / pausal women. Psychoneuroendocrinology, 2003, 28(1): [7] Harman S M, Blackman M R. Use of growth hormone for prevention or treatment of effects of aging. J Gerontol A Biol Sci Med Sci, 2004, 59(7): [8] Obermayr R P, Mayerhofer L, Knechtelsdorfer M,et al. The age-related down-regulation of the growth hormone/ insulin-like growth factor-1 axis in the elderly male is reversed considerably by donepezil, a drug for Alzheimer's disease. Exp Gerontol, 2005, 40(3): [9] Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med, 2002, 346(7): [10] Vitiello M V, Moe K E, Merriam G R. Growth hormone releasing hormone improves the cognition of healthy older adults. Neurobiol Aging, 2006, 27(2): [11] Shin E J, Jhoo J H, Nabeshima T, et al. Growth hormone releaser attenuates β-amyloid (1-42)-induced memory impairment in mice. J Pharmacol Sci, 2005, 99(1): [12] Ghigo E, Nicolosi M, Arvat E, et al. Growth hormone secretion in Alzheimer's disease: studies with growth hormonereleasing hormone alone and combined with pyridostigmine or arginine. Dementia, 1993, 4(6): [13] Arvat E, Gianotti L, Ragusa L, et al. The enhancing effect of pyridostigmine on the GH response to GHRH undergoes an accelerated age-related reduction in Down syndrome. Dementia, 1996, 7(5): [14] Rubin R T, Miller T H, Rhodes M E, et al. Growth hormone responses to low-dose physostigmine in elderly vs. young women and men. Gerontology, 2006, 52(2): [15] Garcia-Segura L M, Perez J, Pons S, et al. Localization of insulin-like growth factor I (IGF-1)-like immunoreactivity in the developing and adult rat brain. Brain Res, 1991, 560(1-2): [16] Lupien S B, Bluhm E J, Ishii D N. Effect of IGF-1 on DNA, RNA, and protein loss associated with brain atrophy and impaired learning in diabetic rats. Neurobiol Dis, 2006, 21: [17] Pulford B E, Ishii D N. Uptake of circulating insulin-like growth factors (IGFs) into cerebrospinal fluid appears to be independent of the IGF receptors as well as IGF binding proteins. Endocrinology, 2001, 142: [18] Zonnor B, Beilharz E J, Williams C, et al. Insulin-like growth factor-1 (IGF-1) immuno reactivity in the Alzheimer s disease temporal cortex and hippocampus. Brain Res Mol Brain Res, 1997, 49(1-2): [19] Alvarez A, Cacabelos R, Sanpedro C. Serum TNF-α levels are increased and correlate negatively with free IGF-1 in Alzheimer disease.neurobiol Aging, 2007, 28(4): [20] Xing C G, Peng Y, Chang R. Effects of insulin-like growth factor-1 on okadaic acid-induced apoptosis in SH-SY5Y cells. Cell Biol Inter, 2005, 29: [21] Carro E, Torres-Aleman I. The role of insulin and insulinlike growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer's disease. Eur J Pharmacol, 2004, 490 (1-3): [22] Schubert M, Brazil D P, Burks D J, et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci, 2003, 23: [23] Born J, Lange T, Kern W, et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci, 2002, 5: [24] Chen X Y, Ferry R J Jr.Novel actions of IGFBP-3 on intracellular signaling pathways of insulin-secreting cells. Growth Horm IGF Res, 2006, 16: [25] Creyghton W M, van Dam P S, Koppeschaar H P.The role of the somatotropic system in cognition and other cerebral functions. Semin Vasc Med, 2004, 4(2): [26] Carro E, Trejo J L, Gerber A, et al. Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiol Aging, 2006, 27(9): [27] Bajpai A, Menon P S. Insulin like growth factors axis and growth disorders. Indian J Pediatr, 2006, 73(1): Trinkaus ,

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