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Etiology of sporadic Alzheimer’s disease: Somatostatin, neprilysin, and amyloid β peptide
Medical Hypotheses (2005) 65, 498–500
http://intl.elsevierhealth.com/journals/mehy
Etiology of sporadic Alzheimer’s disease: Somatostatin, neprilysin, and amyloid b peptide E. Hama, T.C. Saido
*
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan Received 15 February 2005; accepted 19 February 2005
Summary We recently demonstrated that amyloid b peptide (Ab) is catabolized primarily by a neutral endopeptidase, neprilysin, in the brain and that a neuropeptide, somatostatin (SST), regulates brain Ab level via modulation of neprilysin activity. Because SST expression in the brain declines upon aging in various mammals including rodents, apes and humans, we hypothesize that the aging-dependent reduction of SST triggers accumulation of Ab in the brain by suppressing neprilysin action. This hypothesis accounts for the fact that aging is the predominant risk factor for Sporadic Alzheimer’s disease. c 2005 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is the predominant cause of senile dementia. More than one out of two people above the age of 85 are affected by AD or prodromal AD, mild cognitive impairment [1]. AD can be divided into two categories: familial (autosomal dominantly inherited) AD and sporadic AD. The etiology of the former has been established through identification of pathogenic mutations in amyloid precursor protein (APP) and presenilin genes; these mutations cause acceleration of Ab accumulation primarily through increasing the production of the pathogenic form of Ab, Ab42 [2]. The familial AD however accounts for less than 1% of all AD cases. Because there has not been clear evidence for increased production of Ab in sporadic AD cases, because sporadic * Corresponding author. Tel.: +81 48 467 9715; fax: +81 48 467 9716. E-mail address: [email protected] (T.C. Saido).
AD brains accumulate smaller amounts of Ab42 than familial AD brains [3] and because the steady-state levels of Ab in brain can be determined by the balance between anabolism and catabolism, we previously hypothesized that reduced catabolism could be causal for the aging-dependent Ab accumulation in sporadic AD brains [4]. Based on these logics, we identified a neutral endopeptidase, neprilysin, as a major Ab-degrading enzyme and demonstrated that reduction of neprilysin activity leads to increased levels of Ab in the brain in a quantitative manner using neprilysinknockout mice [4,5]. Moreover, we found that neprilysin expression declines in hippocampus and neocortex in a region-specific manner upon aging [6], consistent with the clinical observation that neprilysin expression is selectively reduced in the early stage of AD neuropathology development in hippocampus and temporal cortex, but not in
0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.02.045
Etiology of sporadic Alzheimer’s disease cerebellum, of human brains [7]. We have also demonstrated that some Ab amyloidosis-causing APP mutations within the Ab sequence renders Ab resistant to neprilysin-catalyzed degradation [8]. These observations indicated that the agingdependent decline of neprilysin activity could be causal of Ab accumulation leading to sporadic AD development. We then discovered that a neuropeptide, SST, specifically regulates neuronal neprilysin activity by affecting its expression and synaptic localization [9]. The expression of SST has been known to decline upon aging in various mammals including rodents, apes and humans [10,11]. In human brains, SST mRNA is one of the approximately 50 transcripts, the expression of which significantly declines after the age of 40, among approximately 11,000 transcripts examined [11], indicating that aging-dependent reduction of SST expression is a biologically specific and universal process. These facts, combined with our observations, now lead us propose the following scenario for the etiology of sporadic AD development (Fig. 1). First, the aging-dependent reduction of SST causes a decrease of neprilysin activity, which then causes the steady-state Ab levels in brain to increase. Chronic elevation of the Ab levels may result in further downregulation of SST levels [12], oxidative inactivation of neprilysin [13], increased expression of APP and b-secretase because APP is a stress-responsive protein [14] and expression both APP and b-secretase has been reported to increase in the relatively downstream cascade of AD development [15,16]. These events form a vicious circle leading to a catastrophic accumulation of Ab in the brain [17]. Expression of cortistatin, a recently dis-
Figure 1 Aging, SST, neprilysin and Ab accumulation. The aging-dependent reduction of SST causes a decrease of neprilysin activity, which then causes the steady-state Ab levels in brain to increase. Chronic elevation of the Ab levels may result in further downregulation of SST levels, oxidative inactivation of neprilysin, increased expression of APP and b-secretase. These events form a vicious circle leading to a catastrophic accumulation of Ab in the brain.
499 covered SST-like neuropeptide that can activate SST receptors [18], may also decline upon aging. If this hypothesis turns out to be true, we will not only understand the etiology of sporadic AD but also know a primary strategic target for prevention and treatment of AD.
Acknowledgments Supported by research grants from RIKEN BSI and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
References [1] Golomb J, Kluger A, Ferris SH. Mild cognitive impairment: identifying and treating the earliest stages of Alzheimer’s disease. Neurosci News 2000;3(4):46–53. [2] Duff K, Eckman C, Zehr C, et al. Increased amyloid-b 42 (43) in brains of mice expressing mutant presenilin 1. Nature 1996;383:710–3. [3] Lemere CA, Lopera F, Kosik KS, et al. The E280A Presenilin 1 mutation leads to a distinct Alzheimer’s disease phenotype: increased Ab42 deposition and severe cerebellar pathology. Nat Med 1996;2:1146–50. [4] Iwata N, Tsubuki S, Takaki Y, et al. Identification of the major Ab1–42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 2000;6:143–50. [5] Iwata N, Tsubuki S, Takaki Y, et al. Metabolic regulation of brain Ab by neprilysin. Science 2001;292:1550–2. [6] Iwata N, Takaki Y, Fukami S, et al. Region-specific reduction of Ab-degrading endopeptidase, neprilysin, in mouse hippocampus upon aging. J Neurosci Res 2002;70: 493–500. [7] Yasojima K, Akiyama H, McGeer EG, et al. Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of b-amyloid peptide. Neurosci Lett 2001;297:97–100. [8] Tsubuki S, Takaki Y, Saido TC. Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Ab to physiologically relevant proteolytic degradation. Lancet 2003;361:1957–8. [9] Saito T, Iwata N, Tsubuki S, et al. Somatostatin regulates brain amyloid b peptide Ab42 through modulation of proteolytic degradation. Nat Med 2005;4:434–9. [10] Hayashi M, Yamashita A, Shimizu K. Somatostatin and brain-derived neurotrophic factor mRNA expression in the primate brain: decreased levels of mRNA during aging. Brain Res 1997;749:283–9. [11] Lu T, Pan Y, Kao SY, et al. Gene regulation and DNA damage in the ageing human brain. Nature 2004;429:883–91. [12] Davies P, Katzman R, Terry RD. Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer’s disease and Alzheimer senile dementia. Nature 1980;288:279–80. [13] Wang D-S, Iwata N, Hama E, Saido TC, Dickson DW. Oxidized neprilysin in aging and Alzheimer’s disease brains. Biochem Biophys Res Commun 2003;310: 236–41.
500 [14] Storey E, Capprai R. The amyloid precursor protein of Alzheimer’s disease and the Ab peptide. Neuropathol Appl Neurobiol 1999;25:81–97. [15] Yasojima K, McGeer EG, McGeer PL. Relationship between b amyloid peptide generating molecules and neprilysin in Alzheimer disease and normal brain. Brain Res 2001;919:115–21. [16] Li R, Lindholm K, Yang LB, et al. Amyloid b peptide load is correlated with increased b-secretase activity in sporadic
Hama and Saido Alzheimer’s disease patients. Proc Natl Acad Sci USA 2004;101:3632–7. [17] Funato H, Yoshimura M, Kusui K, et al. Quantitation of amyloid b-protein (Ab) in the cortex during aging and in Alzheimer’s disease. Am J Pathol 1998;152: 1633–1640. [18] Moller LN, Stidsen CE, Hartmann B, Holst JJ. Somatostatin receptors. Biochim Biophys Acta 2003;1616: 1–84.
http://intl.elsevierhealth.com/journals/mehy
Etiology of sporadic Alzheimer’s disease: Somatostatin, neprilysin, and amyloid b peptide E. Hama, T.C. Saido
*
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan Received 15 February 2005; accepted 19 February 2005
Summary We recently demonstrated that amyloid b peptide (Ab) is catabolized primarily by a neutral endopeptidase, neprilysin, in the brain and that a neuropeptide, somatostatin (SST), regulates brain Ab level via modulation of neprilysin activity. Because SST expression in the brain declines upon aging in various mammals including rodents, apes and humans, we hypothesize that the aging-dependent reduction of SST triggers accumulation of Ab in the brain by suppressing neprilysin action. This hypothesis accounts for the fact that aging is the predominant risk factor for Sporadic Alzheimer’s disease. c 2005 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is the predominant cause of senile dementia. More than one out of two people above the age of 85 are affected by AD or prodromal AD, mild cognitive impairment [1]. AD can be divided into two categories: familial (autosomal dominantly inherited) AD and sporadic AD. The etiology of the former has been established through identification of pathogenic mutations in amyloid precursor protein (APP) and presenilin genes; these mutations cause acceleration of Ab accumulation primarily through increasing the production of the pathogenic form of Ab, Ab42 [2]. The familial AD however accounts for less than 1% of all AD cases. Because there has not been clear evidence for increased production of Ab in sporadic AD cases, because sporadic * Corresponding author. Tel.: +81 48 467 9715; fax: +81 48 467 9716. E-mail address: [email protected] (T.C. Saido).
AD brains accumulate smaller amounts of Ab42 than familial AD brains [3] and because the steady-state levels of Ab in brain can be determined by the balance between anabolism and catabolism, we previously hypothesized that reduced catabolism could be causal for the aging-dependent Ab accumulation in sporadic AD brains [4]. Based on these logics, we identified a neutral endopeptidase, neprilysin, as a major Ab-degrading enzyme and demonstrated that reduction of neprilysin activity leads to increased levels of Ab in the brain in a quantitative manner using neprilysinknockout mice [4,5]. Moreover, we found that neprilysin expression declines in hippocampus and neocortex in a region-specific manner upon aging [6], consistent with the clinical observation that neprilysin expression is selectively reduced in the early stage of AD neuropathology development in hippocampus and temporal cortex, but not in
0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.02.045
Etiology of sporadic Alzheimer’s disease cerebellum, of human brains [7]. We have also demonstrated that some Ab amyloidosis-causing APP mutations within the Ab sequence renders Ab resistant to neprilysin-catalyzed degradation [8]. These observations indicated that the agingdependent decline of neprilysin activity could be causal of Ab accumulation leading to sporadic AD development. We then discovered that a neuropeptide, SST, specifically regulates neuronal neprilysin activity by affecting its expression and synaptic localization [9]. The expression of SST has been known to decline upon aging in various mammals including rodents, apes and humans [10,11]. In human brains, SST mRNA is one of the approximately 50 transcripts, the expression of which significantly declines after the age of 40, among approximately 11,000 transcripts examined [11], indicating that aging-dependent reduction of SST expression is a biologically specific and universal process. These facts, combined with our observations, now lead us propose the following scenario for the etiology of sporadic AD development (Fig. 1). First, the aging-dependent reduction of SST causes a decrease of neprilysin activity, which then causes the steady-state Ab levels in brain to increase. Chronic elevation of the Ab levels may result in further downregulation of SST levels [12], oxidative inactivation of neprilysin [13], increased expression of APP and b-secretase because APP is a stress-responsive protein [14] and expression both APP and b-secretase has been reported to increase in the relatively downstream cascade of AD development [15,16]. These events form a vicious circle leading to a catastrophic accumulation of Ab in the brain [17]. Expression of cortistatin, a recently dis-
Figure 1 Aging, SST, neprilysin and Ab accumulation. The aging-dependent reduction of SST causes a decrease of neprilysin activity, which then causes the steady-state Ab levels in brain to increase. Chronic elevation of the Ab levels may result in further downregulation of SST levels, oxidative inactivation of neprilysin, increased expression of APP and b-secretase. These events form a vicious circle leading to a catastrophic accumulation of Ab in the brain.
499 covered SST-like neuropeptide that can activate SST receptors [18], may also decline upon aging. If this hypothesis turns out to be true, we will not only understand the etiology of sporadic AD but also know a primary strategic target for prevention and treatment of AD.
Acknowledgments Supported by research grants from RIKEN BSI and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
References [1] Golomb J, Kluger A, Ferris SH. Mild cognitive impairment: identifying and treating the earliest stages of Alzheimer’s disease. Neurosci News 2000;3(4):46–53. [2] Duff K, Eckman C, Zehr C, et al. Increased amyloid-b 42 (43) in brains of mice expressing mutant presenilin 1. Nature 1996;383:710–3. [3] Lemere CA, Lopera F, Kosik KS, et al. The E280A Presenilin 1 mutation leads to a distinct Alzheimer’s disease phenotype: increased Ab42 deposition and severe cerebellar pathology. Nat Med 1996;2:1146–50. [4] Iwata N, Tsubuki S, Takaki Y, et al. Identification of the major Ab1–42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 2000;6:143–50. [5] Iwata N, Tsubuki S, Takaki Y, et al. Metabolic regulation of brain Ab by neprilysin. Science 2001;292:1550–2. [6] Iwata N, Takaki Y, Fukami S, et al. Region-specific reduction of Ab-degrading endopeptidase, neprilysin, in mouse hippocampus upon aging. J Neurosci Res 2002;70: 493–500. [7] Yasojima K, Akiyama H, McGeer EG, et al. Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of b-amyloid peptide. Neurosci Lett 2001;297:97–100. [8] Tsubuki S, Takaki Y, Saido TC. Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Ab to physiologically relevant proteolytic degradation. Lancet 2003;361:1957–8. [9] Saito T, Iwata N, Tsubuki S, et al. Somatostatin regulates brain amyloid b peptide Ab42 through modulation of proteolytic degradation. Nat Med 2005;4:434–9. [10] Hayashi M, Yamashita A, Shimizu K. Somatostatin and brain-derived neurotrophic factor mRNA expression in the primate brain: decreased levels of mRNA during aging. Brain Res 1997;749:283–9. [11] Lu T, Pan Y, Kao SY, et al. Gene regulation and DNA damage in the ageing human brain. Nature 2004;429:883–91. [12] Davies P, Katzman R, Terry RD. Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer’s disease and Alzheimer senile dementia. Nature 1980;288:279–80. [13] Wang D-S, Iwata N, Hama E, Saido TC, Dickson DW. Oxidized neprilysin in aging and Alzheimer’s disease brains. Biochem Biophys Res Commun 2003;310: 236–41.
500 [14] Storey E, Capprai R. The amyloid precursor protein of Alzheimer’s disease and the Ab peptide. Neuropathol Appl Neurobiol 1999;25:81–97. [15] Yasojima K, McGeer EG, McGeer PL. Relationship between b amyloid peptide generating molecules and neprilysin in Alzheimer disease and normal brain. Brain Res 2001;919:115–21. [16] Li R, Lindholm K, Yang LB, et al. Amyloid b peptide load is correlated with increased b-secretase activity in sporadic
Hama and Saido Alzheimer’s disease patients. Proc Natl Acad Sci USA 2004;101:3632–7. [17] Funato H, Yoshimura M, Kusui K, et al. Quantitation of amyloid b-protein (Ab) in the cortex during aging and in Alzheimer’s disease. Am J Pathol 1998;152: 1633–1640. [18] Moller LN, Stidsen CE, Hartmann B, Holst JJ. Somatostatin receptors. Biochim Biophys Acta 2003;1616: 1–84.