Dysfunction of TGF-β signaling in Alzheimer’s disease

Abstract

Accumulation of β-amyloid peptide (Aβ) 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 Aβ accumulation causes neurodegeneration in AD. In this issue of the JCI, Tesseur et al. report that the expression of TGF-β type II receptor (TβRII) by neurons is reduced very early in the course of AD and that reduced TGF-β signaling increased Aβ deposition and neurodegeneration in a mouse model of AD (see the related article beginning on page 3060). Intriguingly, reduced TGF-β signaling in neuroblastoma cells resulted in neuritic dystrophy and increased levels of secreted Aβ. Collectively, these data suggest that dysfunction of the TGF-β/TβRII signaling axis in the AD brain may accelerate Aβ 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 β-amyloid peptide (Aβ) 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 Aβ accumulation is promoted by changes in the aging brain or whether this is simply a stochastic process associated with aging. Aβ 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 Aβ aggregates may be directly neurotoxic (3, 4). Indeed, a great deal of recent research has focused on small, soluble aggregates of Aβ peptides, termed Aβ oligomers, which can directly alter synaptic function (5, 6). Others have postulated that intracellular deposits of Aβ contribute to AD neurodegeneration (7).

One of the major obstacles limiting our understanding of Aβ-induced pathologies has been the failure to recapitulate a complete AD phenotype in mice in which brain Aβ 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 Aβ 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 Aβ deposits are observed.

Reduced TGF-β 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 Aβ accumulation in AD. These studies, which focused on the TGF-β/ TGF-β type II receptor (TGF-β/TβRII) signaling pathway, demonstrate a role for decreased neuronal TGF-β signaling in age-dependent neurodegeneration and Aβ deposition both in human AD and in AD mouse models. TβRII is a high affinity serine/threonine receptor for TGF-β that signals as part of a complex with activin-like kinase 5 (ALK5; also known as TGF-β type I receptor). The authors performed a detailed analysis of TβRII levels in AD brain tissue and showed that the levels of TβRII are reduced early in the course of the disease. Reduced TβRII levels were found exclusively in AD brain tissue, not in brain tissue affected by any of the several other neurodegenerative conditions analyzed. TGF-β signaling in the brain confers neuroprotection in part by regulating levels of neurotrophins (9); thus, reduced TβRII levels indicate a likely dysfunction in TGF-β–mediated neuroprotective signaling events in the AD brain. Reduced TGF-β signaling, therefore, may lead to neurotrophic factor deficiencies and thus neuronal dysfunction.

Modeling TGF-β signaling in AD mouse models

To further explore the role of TGF-β signaling dysfunction in AD, the authors examined the effects of reducing TβRII signaling by inducibly expressing a kinase-deficient TβRII transgene (TβRIIΔk) in the brains of mice or transiently expressing this kinase-dead receptor in neuroblastoma cells (8). TβRIIΔk expression in the brains of mice resulted in age-dependent neurodegeneration including synaptic loss, dendritic alterations, and neuronal loss. Moreover, expression of TβRIIΔk in human amyloid precursor protein (hAPP) mice significantly enhanced Aβ deposition at 20 months of age but not earlier (i.e., in mice aged 14 months or less). Increases in Aβ deposition did not appear to be attributable to increased production of hAPP, changes in Aβ-degrading enzymes, changes in apoE expression or involvement of microglia, or increased production of Aβ in the young mice. However, TβRIIΔk expression in neuroblastoma cells resulted in beading of neurites, neurite retraction, and rounding of cell bodies — all characteristic features of neurodegeneration — and also increased Aβ production. The increase in Aβ level was associated with increased levels of β-secretase–derived, APP–processing intermediates, suggesting that the TβRIIΔk-induced increase in Aβ level is attributable to enhanced amyloidogenic processing of hAPP. Collectively, these studies suggest that defects in TGF-β signaling may contribute to AD pathogenesis by promoting neurodegeneration and initiating a feedback loop in which the degenerating cell produces more Aβ, thereby enhancing amyloid deposition (Figure 1). At present it is not clear what causes the downregulation of TβRII signaling in AD. Levels of TGF-β and other cytokines are known to be elevated in the AD brain. It is possible that TβRII levels may be downregulated in AD neurons either directly, in response to increased TGF-β levels, or indirectly, in response to other cytokines and/or factors. TβRII downregulation has been observed in a mouse model of focal ischemia (10) and certain cancer cells (11), and one study demonstrated TGF-β–dependent downregulation of TβRII levels (12). It is also not clear precisely how reduced TGF-β signaling alters Aβ processing or whether the observed increase in Aβ production accounts for the increase in deposition in the 20-month-old TβRIIΔk/hAPP mice.

Figure 1. TGF-β signaling in AD.

Aβ accumulates in the AD brain as amyloid within senile plaques and other smaller, soluble aggregates (oligomers). Aβ plaques are associated with a chronic inflammatory state, including reactive astro- and microgliosis and increased production of numerous inflammatory proteins. Chronic inflammation is hypothesized to induce a complex set of changes in neurons that may ultimately lead to neurodegeneration. The neuroprotective cytokine TGF-β is increased in AD and may reduce deposition of Aβ as plaques while enhancing deposition in the cerebral vessels. In this issue of the JCI, Tesseur et al. (8) show that there is reduced TGF-β signaling in the AD brain, which in turn may promote neuronal degeneration by suppression of neurotrophic factor expression or dysfunction of other unknown neuroprotective pathways. Decreased TGF-β signaling in neurons may also increase Aβ levels, enhancing amyloid deposition. Thus, the inflammatory response to Aβ deposits may initiate a positive feedback loop that exacerbates, rather than ameliorates, AD pathology.

Although there are extensive examples in the literature of the deleterious effects of TβRII signaling loss in cells (e.g., TβRII 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-β signaling (8). TGF-β 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-β can modulate amyloid deposition (16) indicate that reestablishment of TGF-β signaling may be a novel therapeutic approach to AD, simultaneously targeting a neurodegenerative pathway and preventing Aβ 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.