TGF-β1 pathway as a new target for neuroprotection in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 37 million people worldwide. Current drugs for AD are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of ß-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. The identification of the molecular determinants underlying AD pathogenesis is a fundamental step to design new disease-modifying drugs. Recently, a specific impairment of transforming-growth-factor-β1 (TGF-β1) signaling pathway has been demonstrated in AD brain. The deficiency of TGF-β1 signaling has been shown to increase both Aβ accumulation and Aβ-induced neurodegeneration in AD models. The loss of function of TGF-ß1 pathway seems also to contribute to tau pathology and neurofibrillary tangle formation. Growing evidence suggests a neuroprotective role for TGF-β1 against Aβ toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF-β1 levels in the central nervous system (CNS), and might be considered as new neuroprotective tools against Aβ-induced neurodegeneration. In the present review, we examine the evidence for a neuroprotective role of TGF-β1 in AD, and discuss the TGF-β1 signaling pathway as a new pharmacological target for the treatment of AD.

Figure 2

Putative mechanisms underlying the neuroprotective effects of TGF‐β1 against Aβ‐induced neurodegeneration. Aβ induces neuronal death via an early activation of cell cycle, and a late induction of DKK1 leading to an inhibition of the canonical Wnt pathway with ensuing activation of GSK‐3β. TGF‐β1 inhibits cell cycle activation and rescues the Wnt pathway via a direct activation of the PI3K pathway. Activation of the classical Smad‐dependent pathway leading to an enhanced expression of cyclin‐dependent kinase inhibitors (p21, p27) and cell cycle arrest is also shown (dotted). Whether this pathway may also contribute to the protective effect of TGF‐β1 against Aβ‐induced neurodegeneration is unknown.

Figure 1

Hypothetical role of TGF‐ß1 in AD pathogenesis. Alterations of TGF‐β1 signaling in AD: (1) a reduced expression of the neuronal TGF‐β type II receptor, (2) a dysfunction of Smad signaling, (3) a reduction in TGF‐β1 plasma levels, (4) an increased occurrence of TGF‐ß1 CC genotype which can promote the conversion of MCI into AD. All alterations might lead to Aβ accumulation and neurofibrillary tangles (NFT) formation with ensuing neurodegeneration.

Figure 3

Lithium stimulates TGF‐β1 release from rat cortical astrocytes. Rat cortical astrocytes were exposed to 1 mM lithium chloride for 24 h, and the incubation medium was collected for western blot analysis (A) and ELISA assay (B). (A) Representative immunoblot of latent TGF‐β1 (about 55 kDa). Protein loading was checked by staining membrane‐transferred proteins with Ponceau's solution. Values are the means ± SEM of 3 determinations; P < 0.05 (by one‐way ANOVA + Fisher's LSD test) versus control (*). (B) Each bar represents the mean ± SEM of active TGF‐β1 protein levels in the incubation medium. Data are from three different experiments; P < 0.05 (by one‐way ANOVA + Fisher's LSD test) versus control (*).