Dysfunction of TGF- signaling in Alzheimer’s disease
http://www.100md.com
《临床调查学报》
Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, Florida, USA.
Abstract
Accumulation of -amyloid peptide (A) in the brain is believed to trigger a complex and poorly understood pathologic reaction that results in the development of Alzheimer’s disease (AD). Despite intensive study, there is no consensus as to how A accumulation causes neurodegeneration in AD. In this issue of the JCI, Tesseur et al. report that the expression of TGF- type II receptor (TRII) by neurons is reduced very early in the course of AD and that reduced TGF- signaling increased A deposition and neurodegeneration in a mouse model of AD (see the related article beginning on page 3060). Intriguingly, reduced TGF- signaling in neuroblastoma cells resulted in neuritic dystrophy and increased levels of secreted A. Collectively, these data suggest that dysfunction of the TGF-/TRII signaling axis in the AD brain may accelerate A deposition and neurodegeneration.
Alzheimer’s disease (AD) is the most common cause of dementia occurring in the elderly. It is characterized pathologically by the deposition of -amyloid peptide (A) in plaques, the development of neurofibrillary tangles (NFTs), and loss of synapses and neurons. Although age is strongly associated with nonautosomal forms of AD, it is not clear whether A accumulation is promoted by changes in the aging brain or whether this is simply a stochastic process associated with aging. A aggregation may cause neurodegeneration through multiple pathways. It has been hypothesized that neurodegeneration results from a chronic inflammatory response to deposited amyloid (1, 2). Alternatively, the various forms of A aggregates may be directly neurotoxic (3, 4). Indeed, a great deal of recent research has focused on small, soluble aggregates of A peptides, termed A oligomers, which can directly alter synaptic function (5, 6). Others have postulated that intracellular deposits of A contribute to AD neurodegeneration (7).
One of the major obstacles limiting our understanding of A-induced pathologies has been the failure to recapitulate a complete AD phenotype in mice in which brain A deposits are observed. Although they recapitulate many features of AD, including the plaque-associated reactive gliosis and neuritic alterations, in the absence of additional manipulations they do not show robust neurodegeneration, irreversible memory loss, or NFT formation. Some AD researchers have used such data to argue that A accumulation does not cause AD. However, many in the field believe that physiologic differences between humans and mice might underlie the lack of a complete AD phenotype in mice in which brain A deposits are observed.
Reduced TGF- signaling in AD
The study by Tesseur et al. (8) in this issue of the JCI provides an elegant example of how identification of molecular changes in the brains of AD patients can be used to guide modeling studies and thereby provide insight into factors that may contribute to neurodegeneration and A accumulation in AD. These studies, which focused on the TGF-/ TGF- type II receptor (TGF-/TRII) signaling pathway, demonstrate a role for decreased neuronal TGF- signaling in age-dependent neurodegeneration and A deposition both in human AD and in AD mouse models. TRII is a high affinity serine/threonine receptor for TGF- that signals as part of a complex with activin-like kinase 5 (ALK5; also known as TGF- type I receptor). The authors performed a detailed analysis of TRII levels in AD brain tissue and showed that the levels of TRII are reduced early in the course of the disease. Reduced TRII levels were found exclusively in AD brain tissue, not in brain tissue affected by any of the several other neurodegenerative conditions analyzed. TGF- signaling in the brain confers neuroprotection in part by regulating levels of neurotrophins (9); thus, reduced TRII levels indicate a likely dysfunction in TGF-–mediated neuroprotective signaling events in the AD brain. Reduced TGF- signaling, therefore, may lead to neurotrophic factor deficiencies and thus neuronal dysfunction.
Modeling TGF- signaling in AD mouse models
To further explore the role of TGF- signaling dysfunction in AD, the authors examined the effects of reducing TRII signaling by inducibly expressing a kinase-deficient TRII transgene (TRIIk) in the brains of mice or transiently expressing this kinase-dead receptor in neuroblastoma cells (8). TRIIk expression in the brains of mice resulted in age-dependent neurodegeneration including synaptic loss, dendritic alterations, and neuronal loss. Moreover, expression of TRIIk in human amyloid precursor protein (hAPP) mice significantly enhanced A deposition at 20 months of age but not earlier (i.e., in mice aged 14 months or less). Increases in A deposition did not appear to be attributable to increased production of hAPP, changes in A-degrading enzymes, changes in apoE expression or involvement of microglia, or increased production of A in the young mice. However, TRIIk expression in neuroblastoma cells resulted in beading of neurites, neurite retraction, and rounding of cell bodies — all characteristic features of neurodegeneration — and also increased A production. The increase in A level was associated with increased levels of -secretase–derived, APP–processing intermediates, suggesting that the TRIIk-induced increase in A level is attributable to enhanced amyloidogenic processing of hAPP. Collectively, these studies suggest that defects in TGF- signaling may contribute to AD pathogenesis by promoting neurodegeneration and initiating a feedback loop in which the degenerating cell produces more A, thereby enhancing amyloid deposition (Figure 1). At present it is not clear what causes the downregulation of TRII signaling in AD. Levels of TGF- and other cytokines are known to be elevated in the AD brain. It is possible that TRII levels may be downregulated in AD neurons either directly, in response to increased TGF- levels, or indirectly, in response to other cytokines and/or factors. TRII downregulation has been observed in a mouse model of focal ischemia (10) and certain cancer cells (11), and one study demonstrated TGF-–dependent downregulation of TRII levels (12). It is also not clear precisely how reduced TGF- signaling alters A processing or whether the observed increase in A production accounts for the increase in deposition in the 20-month-old TRIIk/hAPP mice.
Although there are extensive examples in the literature of the deleterious effects of TRII signaling loss in cells (e.g., TRII knockout in T cells results in uncontrolled T cell proliferation and autoimmune disease; ref. 13), to our knowledge this is the first report to show neurodegeneration due to loss of TGF- signaling (8). TGF- expressed by neurons can protect neurons from CNS inflammation and injury (14) and also play a pivotal role in regulating neuronal development and survival (15). Thus, the results of the present study together with the previous finding of this group that TGF- can modulate amyloid deposition (16) indicate that reestablishment of TGF- signaling may be a novel therapeutic approach to AD, simultaneously targeting a neurodegenerative pathway and preventing A deposition.
On a more general level, these studies highlight the growing recognition that proteins regulating immune function can have significant roles in both the normal and the diseased brain. For example, it was recently reported that an MHC class I receptor plays a critical role in neuronal plasticity (17) and that complement inhibition can enhance plaque deposition and neurodegeneration in mice (18). Future studies examining the role of immune molecules that affect normal aging and disease processes in the CNS are likely to yield novel insights into their functions and roles in CNS diseases.
Footnotes
Nonstandard abbreviations used: A, -amyloid peptide; AD, Alzheimer’s disease; ALK5, activin-like kinase 5; hAPP, human amyloid precursor protein; TRII, TGF- type II receptor; TRIIk, kinase-deficient TRII.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J. Clin. Invest. 116:2855–2857 (2006). doi:10.1172/JCI30284.
See the related article beginning on page 3060.
References
Akiyama H., et al. 2000. Inflammation and Alzheimer’s disease. Neurobiol. Aging. 21:383–421.
Wyss-Coray T. and Mucke L. 2002. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 35:419–432.
Glabe C.C. 2005. Amyloid accumulation and pathogensis of Alzheimer’s disease: significance of monomeric, oligomeric and fibrillar Abeta. Subcell. Biochem. 38:167–177.
Kayed R., et al. 2003. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 300:486–489.
Walsh D.M., et al. 2002. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 416:535–539.
Lesne S., et al. 2006. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 440:352–357.
Billings L.M., Oddo S., Green K.N., McGaugh J.L., Laferla F.M. 2005. Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron. 45:675–688.
Tesseur I., et al. 2006. Deficiency in neuronal TGF- signaling promotes neurodegeneration and Alzheimer’s pathology. J. Clin. Invest. 116:3060–3069. doi:10.1172/JCI27341.
Unsicker K. and Krieglstein K. 2002. TGF-betas and their roles in the regulation of neuron survival. Adv. Exp. Med. Biol. 513:353–374.
Vivien D., et al. 1998. Evidence of type I and type II transforming growth factor-beta receptors in central nervous tissues: changes induced by focal cerebral ischemia. J. Neurochem. 70:2296–2304.
Han G., et al. 2005. Distinct mechanisms of TGF-1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J. Clin. Invest. 115:1714–1723 doi: 10.1172/JCI24399.
Gebken J., et al. 1999. Ligand-induced downregulation of receptors for TGF-beta in human osteoblast-like cells from adult donors. J. Endocrinol. 161:503–510.
Li M.O., Wan Y.Y., Sanjabi S., Robertson A.K., Flavell R.A. 2006. Transforming growth factor-beta regulation of immune responses. Annu. Rev. Immunol. 24:99–146.
Liu Y., Teige I., Birnir B., Issazadeh-Navikas S. 2006. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat. Med. 12:518–525.
Farkas L.M., Dunker N., Roussa E., Unsicker K., Krieglstein K. 2003. Transforming growth factor-beta(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo. J. Neurosci. 23:5178–5186.
Wyss-Coray T., et al. 2001. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat. Med. 7:612–618.
Syken J., Grandpre T., Kanold P.O., Shatz C.J. 2006. PirB restricts ocular-dominance plasticity in visual cortex. Science. In press.
Wyss-Coray T., et al. 2002. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc. Natl. Acad. Sci. U. S. A. 99:10837–10842.(Pritam Das and Todd Golde)
Abstract
Accumulation of -amyloid peptide (A) in the brain is believed to trigger a complex and poorly understood pathologic reaction that results in the development of Alzheimer’s disease (AD). Despite intensive study, there is no consensus as to how A accumulation causes neurodegeneration in AD. In this issue of the JCI, Tesseur et al. report that the expression of TGF- type II receptor (TRII) by neurons is reduced very early in the course of AD and that reduced TGF- signaling increased A deposition and neurodegeneration in a mouse model of AD (see the related article beginning on page 3060). Intriguingly, reduced TGF- signaling in neuroblastoma cells resulted in neuritic dystrophy and increased levels of secreted A. Collectively, these data suggest that dysfunction of the TGF-/TRII signaling axis in the AD brain may accelerate A deposition and neurodegeneration.
Alzheimer’s disease (AD) is the most common cause of dementia occurring in the elderly. It is characterized pathologically by the deposition of -amyloid peptide (A) in plaques, the development of neurofibrillary tangles (NFTs), and loss of synapses and neurons. Although age is strongly associated with nonautosomal forms of AD, it is not clear whether A accumulation is promoted by changes in the aging brain or whether this is simply a stochastic process associated with aging. A aggregation may cause neurodegeneration through multiple pathways. It has been hypothesized that neurodegeneration results from a chronic inflammatory response to deposited amyloid (1, 2). Alternatively, the various forms of A aggregates may be directly neurotoxic (3, 4). Indeed, a great deal of recent research has focused on small, soluble aggregates of A peptides, termed A oligomers, which can directly alter synaptic function (5, 6). Others have postulated that intracellular deposits of A contribute to AD neurodegeneration (7).
One of the major obstacles limiting our understanding of A-induced pathologies has been the failure to recapitulate a complete AD phenotype in mice in which brain A deposits are observed. Although they recapitulate many features of AD, including the plaque-associated reactive gliosis and neuritic alterations, in the absence of additional manipulations they do not show robust neurodegeneration, irreversible memory loss, or NFT formation. Some AD researchers have used such data to argue that A accumulation does not cause AD. However, many in the field believe that physiologic differences between humans and mice might underlie the lack of a complete AD phenotype in mice in which brain A deposits are observed.
Reduced TGF- signaling in AD
The study by Tesseur et al. (8) in this issue of the JCI provides an elegant example of how identification of molecular changes in the brains of AD patients can be used to guide modeling studies and thereby provide insight into factors that may contribute to neurodegeneration and A accumulation in AD. These studies, which focused on the TGF-/ TGF- type II receptor (TGF-/TRII) signaling pathway, demonstrate a role for decreased neuronal TGF- signaling in age-dependent neurodegeneration and A deposition both in human AD and in AD mouse models. TRII is a high affinity serine/threonine receptor for TGF- that signals as part of a complex with activin-like kinase 5 (ALK5; also known as TGF- type I receptor). The authors performed a detailed analysis of TRII levels in AD brain tissue and showed that the levels of TRII are reduced early in the course of the disease. Reduced TRII levels were found exclusively in AD brain tissue, not in brain tissue affected by any of the several other neurodegenerative conditions analyzed. TGF- signaling in the brain confers neuroprotection in part by regulating levels of neurotrophins (9); thus, reduced TRII levels indicate a likely dysfunction in TGF-–mediated neuroprotective signaling events in the AD brain. Reduced TGF- signaling, therefore, may lead to neurotrophic factor deficiencies and thus neuronal dysfunction.
Modeling TGF- signaling in AD mouse models
To further explore the role of TGF- signaling dysfunction in AD, the authors examined the effects of reducing TRII signaling by inducibly expressing a kinase-deficient TRII transgene (TRIIk) in the brains of mice or transiently expressing this kinase-dead receptor in neuroblastoma cells (8). TRIIk expression in the brains of mice resulted in age-dependent neurodegeneration including synaptic loss, dendritic alterations, and neuronal loss. Moreover, expression of TRIIk in human amyloid precursor protein (hAPP) mice significantly enhanced A deposition at 20 months of age but not earlier (i.e., in mice aged 14 months or less). Increases in A deposition did not appear to be attributable to increased production of hAPP, changes in A-degrading enzymes, changes in apoE expression or involvement of microglia, or increased production of A in the young mice. However, TRIIk expression in neuroblastoma cells resulted in beading of neurites, neurite retraction, and rounding of cell bodies — all characteristic features of neurodegeneration — and also increased A production. The increase in A level was associated with increased levels of -secretase–derived, APP–processing intermediates, suggesting that the TRIIk-induced increase in A level is attributable to enhanced amyloidogenic processing of hAPP. Collectively, these studies suggest that defects in TGF- signaling may contribute to AD pathogenesis by promoting neurodegeneration and initiating a feedback loop in which the degenerating cell produces more A, thereby enhancing amyloid deposition (Figure 1). At present it is not clear what causes the downregulation of TRII signaling in AD. Levels of TGF- and other cytokines are known to be elevated in the AD brain. It is possible that TRII levels may be downregulated in AD neurons either directly, in response to increased TGF- levels, or indirectly, in response to other cytokines and/or factors. TRII downregulation has been observed in a mouse model of focal ischemia (10) and certain cancer cells (11), and one study demonstrated TGF-–dependent downregulation of TRII levels (12). It is also not clear precisely how reduced TGF- signaling alters A processing or whether the observed increase in A production accounts for the increase in deposition in the 20-month-old TRIIk/hAPP mice.
Although there are extensive examples in the literature of the deleterious effects of TRII signaling loss in cells (e.g., TRII knockout in T cells results in uncontrolled T cell proliferation and autoimmune disease; ref. 13), to our knowledge this is the first report to show neurodegeneration due to loss of TGF- signaling (8). TGF- expressed by neurons can protect neurons from CNS inflammation and injury (14) and also play a pivotal role in regulating neuronal development and survival (15). Thus, the results of the present study together with the previous finding of this group that TGF- can modulate amyloid deposition (16) indicate that reestablishment of TGF- signaling may be a novel therapeutic approach to AD, simultaneously targeting a neurodegenerative pathway and preventing A deposition.
On a more general level, these studies highlight the growing recognition that proteins regulating immune function can have significant roles in both the normal and the diseased brain. For example, it was recently reported that an MHC class I receptor plays a critical role in neuronal plasticity (17) and that complement inhibition can enhance plaque deposition and neurodegeneration in mice (18). Future studies examining the role of immune molecules that affect normal aging and disease processes in the CNS are likely to yield novel insights into their functions and roles in CNS diseases.
Footnotes
Nonstandard abbreviations used: A, -amyloid peptide; AD, Alzheimer’s disease; ALK5, activin-like kinase 5; hAPP, human amyloid precursor protein; TRII, TGF- type II receptor; TRIIk, kinase-deficient TRII.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J. Clin. Invest. 116:2855–2857 (2006). doi:10.1172/JCI30284.
See the related article beginning on page 3060.
References
Akiyama H., et al. 2000. Inflammation and Alzheimer’s disease. Neurobiol. Aging. 21:383–421.
Wyss-Coray T. and Mucke L. 2002. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 35:419–432.
Glabe C.C. 2005. Amyloid accumulation and pathogensis of Alzheimer’s disease: significance of monomeric, oligomeric and fibrillar Abeta. Subcell. Biochem. 38:167–177.
Kayed R., et al. 2003. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 300:486–489.
Walsh D.M., et al. 2002. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 416:535–539.
Lesne S., et al. 2006. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 440:352–357.
Billings L.M., Oddo S., Green K.N., McGaugh J.L., Laferla F.M. 2005. Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron. 45:675–688.
Tesseur I., et al. 2006. Deficiency in neuronal TGF- signaling promotes neurodegeneration and Alzheimer’s pathology. J. Clin. Invest. 116:3060–3069. doi:10.1172/JCI27341.
Unsicker K. and Krieglstein K. 2002. TGF-betas and their roles in the regulation of neuron survival. Adv. Exp. Med. Biol. 513:353–374.
Vivien D., et al. 1998. Evidence of type I and type II transforming growth factor-beta receptors in central nervous tissues: changes induced by focal cerebral ischemia. J. Neurochem. 70:2296–2304.
Han G., et al. 2005. Distinct mechanisms of TGF-1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J. Clin. Invest. 115:1714–1723 doi: 10.1172/JCI24399.
Gebken J., et al. 1999. Ligand-induced downregulation of receptors for TGF-beta in human osteoblast-like cells from adult donors. J. Endocrinol. 161:503–510.
Li M.O., Wan Y.Y., Sanjabi S., Robertson A.K., Flavell R.A. 2006. Transforming growth factor-beta regulation of immune responses. Annu. Rev. Immunol. 24:99–146.
Liu Y., Teige I., Birnir B., Issazadeh-Navikas S. 2006. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat. Med. 12:518–525.
Farkas L.M., Dunker N., Roussa E., Unsicker K., Krieglstein K. 2003. Transforming growth factor-beta(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo. J. Neurosci. 23:5178–5186.
Wyss-Coray T., et al. 2001. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat. Med. 7:612–618.
Syken J., Grandpre T., Kanold P.O., Shatz C.J. 2006. PirB restricts ocular-dominance plasticity in visual cortex. Science. In press.
Wyss-Coray T., et al. 2002. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc. Natl. Acad. Sci. U. S. A. 99:10837–10842.(Pritam Das and Todd Golde)