These new findings support the idea that glial interferon-γ and TNFα enhance Aβ deposition through BACE1 expression and suppression of Aβ clearance. They provide another piece of experimental evidence linking TNFα to AD pathogenesis. The authors conclude, based on their experimental results, that “Therapeutic strategies that reduce levels of proinflammatory cytokines and BACE1 could lead to attenuation of glial β-amyloid and could lead to novel strategies for AD treatment.” This conclusion is concordant with a recent collaborative work published in the Archives of Neurology, which suggested that TNFα polymorphisms were linked to AD risk, and in which those authors concluded, “The data support that therapeutic strategies designed to reduce TNFα protein production or activity might be a valuable treatment for AD.” [1]

Of related interest is the suggestion that cerebrovascular dysfunction is involved in the pathogenesis of AD [2]. This suggestion is supported by experimental findings that cerebrovascular Aβ deposition induces vascular degeneration and neuroinflammation in...  Read more

These new findings support the idea that glial interferon-γ and TNFα enhance Aβ deposition through BACE1 expression and suppression of Aβ clearance. They provide another piece of experimental evidence linking TNFα to AD pathogenesis. The authors conclude, based on their experimental results, that “Therapeutic strategies that reduce levels of proinflammatory cytokines and BACE1 could lead to attenuation of glial β-amyloid and could lead to novel strategies for AD treatment.” This conclusion is concordant with a recent collaborative work published in the Archives of Neurology, which suggested that TNFα polymorphisms were linked to AD risk, and in which those authors concluded, “The data support that therapeutic strategies designed to reduce TNFα protein production or activity might be a valuable treatment for AD.” [1]

Of related interest is the suggestion that cerebrovascular dysfunction is involved in the pathogenesis of AD [2]. This suggestion is supported by experimental findings that cerebrovascular Aβ deposition induces vascular degeneration and neuroinflammation in transgenic mice [3], and by a substantial body of additional evidence [4].

New experimental evidence suggests that anti-TNFα treatment may be of potential benefit in this regard, also [5]. Aged rats were treated with etanercept, which attenuated age-related vascular changes, and the authors conclude that “vasculoprotective effects of anti-TNFα treatments may be beneficial in elderly patients.” [5]

These collective findings add to a growing body of evidence that provides scientific support for the positive clinical effects my colleagues and I documented in our recent pilot study of perispinal etanercept in Alzheimer disease [6]. In addition, these collective findings support the long-held notion that neuroinflammation mediated by TNFα interacts with amyloid-mediated mechanisms in the pathogenesis of AD [7-16]. Perhaps it is time that a “TNFα hypothesis” joins the “amyloid-cascade hypothesis” in the minds of the Alzheimer research community. Certainly further research in this promising therapeutic area is immediately warranted.

References:
1. Ramos EM, Lin MT, Larson EB, Maezawa I, Tseng LH, Edwards KL, Schellenberg GD, Hansen JA, Kukull WA, Jin LW. Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol. 2006 Aug;63(8):1165-9. Abstract

2. Lopez-Lopez C, Dietrich MO, Metzger F, Loetscher H, Torres-Aleman I. Disturbed cross talk between insulin-like growth factor I and AMP-activated protein kinase as a possible cause of vascular dysfunction in the amyloid precursor protein/presenilin 2 mouse model of Alzheimer's disease. J Neurosci. 2007 Jan 24;27(4):824-31. Abstract

3. Miao J, Xu F, Davis J, Otte-Holler I, Verbeek MM, Van Nostrand WE. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005 Aug;167(2):505-15. Abstract

4. de la Torre JC. Impaired cerebromicrovascular perfusion. Summary of evidence in support of its causality in Alzheimer's disease. Ann N Y Acad Sci. 2000;924:136-52. Review. Abstract

5. Csiszar A, Labinskyy N, Smith K, Rivera A, Orosz Z, Ungvari Z. Vasculoprotective effects of anti-tumor necrosis factor-alpha treatment in aging. Am J Pathol. 2007 Jan;170(1):388-98. Abstract

6. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006 Apr 26;8(2):25. Abstract

7. Klegeris A, Walker DG, McGeer PL. Interaction of Alzheimer beta-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-alpha. Brain Res. 1997 Jan 30;747(1):114-21. Abstract

8. Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B. TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J. 1999 Jan;13(1):63-8. Abstract

9. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and Alzheimer's disease. Neurobiol Aging. 2000 May-Jun;21(3):383-421. Review. Abstract

10. Cooper NR, Kalaria RN, McGeer PL, Rogers J. Key issues in Alzheimer's disease inflammation. Neurobiol Aging. 2000 May 1;21(3):451-453. No abstract available. Abstract

11. Thal LJ. Anti-inflammatory drugs and Alzheimer's disease. Neurobiol Aging. 2000 May-Jun;21(3):449-50; discussion 451-3. No abstract available. Abstract

12. Combs CK, Karlo JC, Kao SC, Landreth GE. beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci. 2001 Feb 15;21(4):1179-88. Abstract

13. Floden AM, Li S, Combs CK. Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors. J Neurosci. 2005 Mar 9;25(10):2566-75. Abstract

14. Laws SM, Perneczky R, Wagenpfeil S, Muller U, Forstl H, Martins RN, Kurz A, Riemenschneider M. TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels. Hum Mutat. 2005 Jul;26(1):29-35. Abstract

15. Mbebi C, Gonzalez de Aguilar JL, See V, Dupuis L, Frossard N, Mercken L, Pradier L, Larmet Y, Loeffler JP. Antibody-bound beta-amyloid precursor protein stimulates the production of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 by cortical neurons. Neurobiol Dis. 2005 Jun-Jul;19(1-2):129-41. Abstract

16. Rosenberg PB. Clinical aspects of inflammation in Alzheimer's disease. Int Rev Psychiatry. 2005 Dec;17(6):503-14. Review. Abstract

View all comments by E T

Comment by Magdalena Sastre; coauthors Michael Heneka and Fred Van Leuven
The results accrued by Yamamoto and colleagues are most interesting as they independently and fully support our own published data (Sastre et al., 2003; Heneka et al., 2005; Sastre et al., 2006) and thereby strongly endorse the hypothesis that inflammation plays a major part in the pathogenesis of AD.

We showed that cytokines transcriptionally upregulate the β-secretase (BACE1) gene, resulting in increased mRNA, protein, and enzymatic activity in N2a cells (Sastre et al., 2003). Those data are completely in line with the increased expression and activity of BACE1 1) in NT2 neurons exposed to oxidative stress (Tamagno et al., 2002), 2) in experimental traumatic brain injury (Blasko et al., 2004), and 3) in reactive astrocytes in chronic models of gliosis (Hartlage-Rübsamen et al., 2003).

We have recently identified in the BACE1 gene promoter a consensus binding site for PPARγ, and our reporter gene assays demonstrated that PPARγ is a repressor of BACE1 expression (Sastre et al., 2006)....  Read more

Comment by Magdalena Sastre; coauthors Michael Heneka and Fred Van Leuven
The results accrued by Yamamoto and colleagues are most interesting as they independently and fully support our own published data (Sastre et al., 2003; Heneka et al., 2005; Sastre et al., 2006) and thereby strongly endorse the hypothesis that inflammation plays a major part in the pathogenesis of AD.

We showed that cytokines transcriptionally upregulate the β-secretase (BACE1) gene, resulting in increased mRNA, protein, and enzymatic activity in N2a cells (Sastre et al., 2003). Those data are completely in line with the increased expression and activity of BACE1 1) in NT2 neurons exposed to oxidative stress (Tamagno et al., 2002), 2) in experimental traumatic brain injury (Blasko et al., 2004), and 3) in reactive astrocytes in chronic models of gliosis (Hartlage-Rübsamen et al., 2003).

We have recently identified in the BACE1 gene promoter a consensus binding site for PPARγ, and our reporter gene assays demonstrated that PPARγ is a repressor of BACE1 expression (Sastre et al., 2006). PPARγ levels are modulated by inflammatory cytokines that affect BACE1 transcription (Sastre et al., 2006). Furthermore, we demonstrated that certain NSAIDs that are also PPARγ activators decrease BACE1 transcription, expression, and activity (Sastre et al., 2003; Heneka et al., 2005).

Another closely related mechanism, described recently, involves IFNγ regulation of BACE1 expression in astrocytes, via the activation of JAK2 and ERK1/2 signaling pathways and the direct binding of STAT1 to the BACE1 gene promoter (Cho et al., 2007).

Yamamoto and colleagues now show that IFNγ and TNFα directly stimulate BACE1 expression in wild-type astrocytes, but not in astrocytes from mice lacking IFNγ receptor type-1. We appreciate the data. Beyond that, we would have liked to also see a thorough discussion and relation to our and other reports that already had studied the molecular basis underlying the BACE1 regulation. We consider the current results of Yamamoto et al. (2007) of sufficient interest to recommend them in the context of existing literature.

References:
Blasko I, Beer R, Bigl M, Apelt J, Franz G, Rudzki D, Ransmayr G, Kampfl A, Schliebs R. Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer's disease beta-secretase (BACE-1). J Neural Transm. 2004 Apr;111(4):523-36. Epub 2004 Feb 4. Abstract

Cho HJ, Kim SK, Jin SM, Hwang EM, Kim YS, Huh K, Mook-Jung I. IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes. Glia. 2007 Feb;55(3):253-62. Abstract

Hartlage-Rubsamen M, Zeitschel U, Apelt J, Gartner U, Franke H, Stahl T, Gunther A, Schliebs R, Penkowa M, Bigl V, Rossner S. Astrocytic expression of the Alzheimer's disease beta-secretase (BACE1) is stimulus-dependent. Glia. 2003 Jan 15;41(2):169-79. Abstract

Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O'Banion K, Klockgether T, Van Leuven F, Landreth GE. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain. 2005 Jun;128(Pt 6):1442-53. Epub 2005 Apr 7. Abstract

Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR. Alzheimer's disease beta-secretase BACE1 is not a neuron-specific enzyme. J Neurochem. 2005 Jan;92(2):226-34. Review. Abstract

Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci. 2003 Oct 29;23(30):9796-804. Abstract

Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J, Klockgether T, van Leuven F, Heneka MT. Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):443-8. Epub 2006 Jan 3. Abstract

Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002 Aug;10(3):279-88. Abstract

View all comments by Magdalena Sastre

We would like to thank Drs. Tobinick, Sastre, and colleagues for their constructive comments. In accord, all of these studies are pointing to the importance of anti-inflammatory therapy for preventing gliosis-mediated Aβ production. Since accelerated gliosis is closely associated with aging, this may be a mechanism of aging-related onset of AD. TNF may be one of the players in understanding the mechanism, since CD40L, another TNF superfamily molecule, is also involved in the β-processing of APP in vivo (Tan et al., 2004). Thus, full characterization of the TNF superfamily would be very important for understanding the gliosis-mediated upregulation of Aβ production, more specifically BACE1 activity.

We are also encouraged by the success of a recent open-label trial of the TNF inhibitor (Etanercept) in AD patients (Tobinick et al., 2006). These studies strongly support the clinical application of TNF inhibitors or other anti-inflammatory therapy on AD patients. In-vitro screening of NSAIDs based on the suppression of BACE promoter activity might be a promising strategy for...  Read more

We would like to thank Drs. Tobinick, Sastre, and colleagues for their constructive comments. In accord, all of these studies are pointing to the importance of anti-inflammatory therapy for preventing gliosis-mediated Aβ production. Since accelerated gliosis is closely associated with aging, this may be a mechanism of aging-related onset of AD. TNF may be one of the players in understanding the mechanism, since CD40L, another TNF superfamily molecule, is also involved in the β-processing of APP in vivo (Tan et al., 2004). Thus, full characterization of the TNF superfamily would be very important for understanding the gliosis-mediated upregulation of Aβ production, more specifically BACE1 activity.

We are also encouraged by the success of a recent open-label trial of the TNF inhibitor (Etanercept) in AD patients (Tobinick et al., 2006). These studies strongly support the clinical application of TNF inhibitors or other anti-inflammatory therapy on AD patients. In-vitro screening of NSAIDs based on the suppression of BACE promoter activity might be a promising strategy for high-throughput screening of therapeutic compounds.

References:
Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science. 1999 Dec 17;286(5448):2352-5. Abstract

Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006 Apr 26;8(2):25. Abstract

View all comments by Tsuneya Ikezu