Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology

Abstract

Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the β-amyloid peptide (Aβ), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-β type II receptor (TβRII) is mainly expressed by neurons, and that TβRII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-β signaling in mice resulted in age-dependent neurodegeneration and promoted Aβ accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-β signaling caused neuronal degeneration and resulted in increased levels of secreted Aβ and β-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-β signaling increases age-dependent neurodegeneration and AD-like disease in vivo. Increasing neuronal TGF-β signaling may thus reduce neurodegeneration and be beneficial in AD. IntroductionAlzheimer's disease (AD) is a progressive neurodegenerative disease that leads to loss of cognitive function in a large number of elderly people. The human AD brain is characterized by the accumulation of β-amyloid peptide (Aβ) in extracellular plaques and hyperphosphorylated tau in intracellular neurofibrillary tangles. In addition, there is degeneration of synapses and dendrites and a progressive loss of neurons involved in memory processes (1). The cause of this degeneration in AD remains unknown, and no effective treatments are available.Survival of neurons is dependent on extracellular signals from neurotrophic factors and related factors with trophic activity (reviewed in ref.2). Levels of the neurotrophin nerve growth factor (NGF) and its receptor, tropomyosin receptor kinase A (TRKA), as well as levels of brain-derived neurotrophic factor (BDNF) and its receptor, TRKB, are lower in human AD brains than in nondemented controls (2-5). It was therefore proposed that a deficiency in neurotrophic factor signaling would promote neurodegeneration and cognitive dysfunction in AD, but this hypothesis has not been tested using specific genetic inhibition of neurotrophic factor signaling in a mouse model for AD (reviewed in refs. 2, 6).

HtrA1-dependent proteolysis of TGF-β controls both neuronal maturation and developmental survival

“…34 At the opposite, a deficiency in neuronal TGF-b signalling was reported to promote neurodegeneration and Alzheimer's pathology. 33 Interestingly, HtrA1 was also directly involved in the b-amyloid pathway, in which HtrA1 colocalizes with b-amyloid deposits in human brain samples and reduces Ab accumulation in astrocytes cell culture supernatants. 15 In parallel, we have previously demonstrated that TGF-b treatment in both murine and human cultured astrocytes leads to an increased transcription of APP and subsequent accumulation of Ab.…”

“…32 Similarly, although it has been proposed that AD is accompanied by increased TGF-b levels within the brain parenchyma, 31 a recent report suggests that TGF-b signalling might be downregulated due to a reduced expression of its TbR-II receptor. 33 Similarly, conflicting data have been published regarding the potential role of altered TGF-b levels in AD. For instance, in human amyloid precursor protein (hAPP) transgenic mice, a moderate increase in astrocytic expression of TGF-b1 was proposed to lead to a reduced Ab accumulation because of a TGF-b-dependent phagocytosis of Ab by microglia.…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…Interestingly, TGF-b1 is enriched in plasma lipoprotein samples of apoliprotein E3 (apoE3), but occurs at a lower concentration in lipoproteins containing apoE4, a genetic risk factor for late-onset Alzheimer's disease (Tesseur et al 2009;Bertram et al 2010). Impairment in TGF-b/Smad signaling and decreased neuronal expression of TbRII are both characteristics of disease pathology, providing further evidence for a role for TGF-b in Alzheimer's disease (Tesseur et al 2006;Ueberham et al 2006;Wang et al 2010).…”

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

“…TGF-b signaling has been reported to be insufficient in the brains of AD patients [123]. This deficiency has been shown to cause more Ab deposition and neurodegeneration [123], while treatment with TGF-b prevents Ab-induced neurotoxicity [124].…”