Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are members of the neurotrophin family that normally play a role in the development and maintenance of the nervous system. However, neurotrophin dysregulation has been implicated in several neurodegenerative diseases and psychiatric disorders including Alzheimer's disease, Parkinson's disease, neuropathic pain, depression, and substance abuse. Despite their central role in the nervous system, neurotrophins have proved to be an elusive pharmacological target. Here, we describe a novel multipotent neurotrophin antagonist Y1036 prevents both BDNF-and NGF-mediated trk activation, downstream activation of the p44/42 mitogen-activated protein kinase pathway, and neurotrophin-mediated differentiation of dorsal-root ganglion sensory neurons. Identification of a BDNF-and NGF-specific antagonist is of considerable interest in the study and treatment of diseases where dysregulation of multiple neurotrophins has been implicated.

Transforming growth factor-␤ (TGF-␤) receptor-mediated signaling has been proposed to mediate both the beneficial and deleterious roles for this cytokine in amyloid-␤ protein (A␤) function. In order to assess receptor dependence of these events, we used PC12 cell cultures, which are devoid of TGF-␤ receptors. Surprisingly, TGF-␤ potentiated the neurotoxic effects of the 40-residue A␤ peptide, A␤-(1-40), in this model suggesting that there may be a direct, receptor-independent interaction between TGF-␤ and A␤-(1-40). Surface plasmon resonance confirmed that TGF-␤ binds with high affinity directly to A␤-(1-40) and electron microscopy revealed that TGF-␤ enhances A␤-(1-40) oligomerization. Immunohistochemical examination of mouse brain revealed that hippocampal CA1 and dentate gyrus, two regions classically associated with A␤-mediated pathology, lack TGF-␤ Type I receptor immunoreactivity, thus indicating that TGF-␤ receptor-mediated signaling would not be favored in these regions. Our observations not only provide for a unique, receptor-independent mechanism of action for TGF-␤, but also help to reconcile the literature interpreting the role of TGF-␤ in A␤ function. These data support a critical etiological role for this mechanism in neuropathological amyloidoses.