In normal adult retinas, NGF receptor TrkA is expressed in retinal ganglion cells (RGC), whereas glia express p75NTR . During retinal injury, endogenous NGF, TrkA, and p75 NTR are up-regulated. Paradoxically, neither endogenous NGF nor exogenous administration of wild type NGF can protect degenerating RGCs, even when administered at high frequency. Here we elucidate the relative contribution of NGF and each of its receptors to RGC degeneration in vivo. During retinal degeneration due to glaucoma or optic nerve transection, treatment with a mutant NGF that only activates TrkA, or with a biological response modifier that prevents endogenous NGF and pro-NGF from binding to p75 NTR affords significant neuroprotection. Treatment of normal eyes with an NGF mutant-selective p75 NTR agonist causes progressive RGC death, and in injured eyes it accelerates RGC death. The mechanism of p75 NTR action during retinal degeneration due to glaucoma is paracrine, by increasing production of neurotoxic proteins TNF-␣ and ␣ 2 -macroglobulin. Antagonists of p75 NTR inhibit TNF-␣ and ␣ 2 -macroglobulin up-regulation during disease, and afford neuroprotection. These data reveal a balance of neuroprotective and neurotoxic mechanisms in normal and diseased retinas, and validate each neurotrophin receptor as a pharmacological target for neuroprotection.Neuropathic diseases of the retina that involve the death of retinal ganglion cells (RGCs) 4 are irreversible. This is because RGCs are neurons whose fibers and axons make up the optic nerve (ON) and relay visual input from the retina to the cerebral cortex.Commonly used animal models of neuropathy that cause RGC death include ON axotomy and glaucoma. ON axotomy is an acute model of trauma where the optic nerve is completely severed, causing rapid death of the RGCs (ϳ90% within 2 weeks). Glaucoma is a chronic and progressive optic nerve neuropathy often concomitant with elevated intraocular pressure (IOP) (1). The etiology of RGC death in glaucoma remains unknown.One mechanism is the deprivation of survival signals that neurotrophins provide by acting through the TrkA and TrkB receptors expressed in RGCs (2, 3). Indeed, activation of TrkA (4) or TrkB (5) directly activate pro-survival signals during glaucoma and rescues RGCs from death during ON axotomy or glaucoma. However, it seems paradoxical that whereas TrkA activity is protective, neither endogenous nerve growth factor (NGF) (up-regulated in glaucoma (6)) nor exogenous NGF applied as a drug afford effective RGC neuroprotection during ON axotomy or glaucoma (4, 7).A second mechanism of RGC death in glaucoma is the increased production of tumor necrosis factor-␣ (TNF-␣) (8-10) and ␣ 2 -macroglobulin (␣ 2 M) (11). These neurotoxic factors are produced by activated microglia (12), which express the neurotrophin receptor p75 NTR (7). Indeed, the p75 NTR receptor has been implicated in the acute release of TNF-␣ during acute toxicity leading to RGC death within a few hours after intravitreal injection of glutamate (13) or after activatio...

The degeneration of cholinergic neurons is a prominent feature of Alzheimer’s disease (AD). In animal models of injury and aging, nerve growth factor (NGF) enhances cholinergic cell survival and function, contributing to improved memory. In the presence of AD pathology, however, NGF-related therapeutics have yet to fulfill their regenerative potential. We propose that stimulating the TrkA receptor, without p75NTR activation, is key for therapeutic efficacy. Supporting this hypothesis, the selective TrkA agonist D3 rescued neurotrophin signaling in TgCRND8 mice, whereas NGF, interacting with both TrkA and p75NTR, did not. D3, delivered intravenously and noninvasively to the basal forebrain using MRI-guided focused ultrasound (MRIgFUS)–mediated blood-brain barrier (BBB) permeability activated TrkA-related signaling cascades and enhanced cholinergic neurotransmission. Recent clinical trials support the safety and feasibility of MRIgFUS BBB modulation in AD patients. Neuroprotective agents targeting TrkA, combined with MRIgFUS BBB modulation, represent a promising strategy to counter neurodegeneration in AD.

HER2 is a validated therapeutic target for cancer. There are no natural ligands, but monoclonal antibodies and peptides that bind HER2 act as artificial ligands, selectively affecting HER2-overexpressing tumors. One reported mechanism for this effect is receptor downregulation, but the expected correlation of ligand-dependent HER2 internalization and tumor inhibition remain poorly characterized. Moreover, HER2 ligands have limited therapeutic efficacy and often they require adjuvant treatment with the chemotherapeutic Taxol. Here, we generated a series of HER2 ligands (Anti-HER2/neu peptide ligands, AHNPmonovalent and AHNPbivalent) with different valency and correlated their internalization-promoting ability to biological potency. Since AHNPbivalent (but not AHNPmonovalent) induces rapid receptor internalization, we exploited this feature to deliver cytotoxic conjugates coupling AHNPbivalent and Taxol (Taxol . AHNPbivalent). The prodrug conjugate releases Taxol after receptor-mediated internalization, and cytotoxicity can be used as a marker of internalization. Taxol . AHNPbivalent is significantly more cytotoxic than free Taxol + free AHNPbivalent. Hence, the Taxol x AHNP(bivalent) prodrug binds to HER2, induces receptor internalization and downregulation, and the subsequent release of free Taxol inside the targeted cell results in synergistic toxicity, The effect is selective towards HER2- expressing cells. This work links HER2 receptor internalization and growth arrest, and the chemical conjugation strategy may yield improved and HER2 selective therapeutics.