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Alzheimer's disease is characterized by the accumulation of neurotoxic amyloidogenic peptide A␤, degeneration of the cholinergic innervation to the hippocampus (the septohippocampal pathway), and progressive impairment of cognitive function, particularly memory. A␤ is a ligand for the p75 neurotrophin receptor (p75 NTR ), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimer's disease. Here we examined whether p75 NTR is required for A␤-mediated effects. Treatment of wild-type but not p75 NTR -deficient embryonic mouse hippocampal neurons with human A␤ 1-42 peptide induced significant cell death. Furthermore, injection of A␤ 1-42 into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75 NTR -deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to A␤-induced toxicity. We also found that neuronal death correlated with A␤ 1-42 peptide-stimulated accumulation of the death-inducing p75 NTR C-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75 NTR . Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor-␣ protease inhibitor-2), A␤ 1-42 -induced accumulation of the C-terminal fragment resulted from inhibition of ␥-secretase activity. These results provide a novel mechanism to explain the early and characteristic loss of cholinergic neurons in the septohippocampal pathway that occurs in Alzheimer's disease.

Transit of proteins through the endosomal organelle following endocytosis is critical for regulating the homeostasis of cell-surface proteins and controlling signal transduction pathways. However, the mechanisms that control these membrane-transport processes are poorly understood. The Phox-homology (PX) domain-containing proteins sorting nexin (SNX) 17, SNX27, and SNX31 have emerged recently as key regulators of endosomal recycling and bind conserved Asn-Pro-Xaa-Tyr-sorting signals in transmembrane cargos via an atypical band, 4.1/ezrin/radixin/moesin (FERM) domain. Here we present the crystal structure of the SNX17 FERM domain bound to the sorting motif of the P-selectin adhesion protein, revealing both the architecture of the atypical FERM domain and the molecular basis for recognition of these essential sorting sequences. We further show that the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins.endosome | protein crystallography | X-ray scattering | membrane trafficking T he cell-surface levels of signaling and adhesion receptors, nutrient transporters, ion channels, and many other proteins are tightly regulated by opposing endocytic, exocytic, and endosomal recycling transport pathways. The selective sorting of these transmembrane proteins is the consequence of their interaction with essential adaptor proteins via conserved motifs present in their cytosolic tails, generally based on short linear amino acid sequences such as the Yxxϕ, DxxLL, and [DE]xxxL [LI] motifs (where ϕ is any bulky hydrophobic side-chain, and x is any residue) recognized by clathrin adaptors (1-3). The first identified sorting signal was the Asn-Pro-Xaa-Tyr (NPxY) motif, initially described in the LDL receptor (LDLR) isolated from patients suffering from familial hypercholesterolemia, where mutation of the sequence results in defective internalization and cholesterol uptake (4). The recent structure of the autosomal recessive hypercholesterolemia protein (ARH) phosphotyrosinebinding (PTB) domain in complex with the LDLR intracellular domain (ICD) provides the molecular basis of LDLR recognition and internalization within clathrin-coated pits by endocytic adaptor proteins (5).Although little is known about the sorting sequences and mechanisms required for competing endosome-to-cell surface recycling pathways, emerging evidence shows that the NPxY motif not only is vital to internalization but also aids cargo recycling via organelle-specific recognition by the endosomal protein, sorting nexin 17 (SNX17). SNX17 is a member of the Phox-homology (PX) domain-containing protein family and has been shown to be a critical regulator of endosomal sorting and cell-surface recycling of several essential cargo molecules. These include P-selectin (6-8), amyloid precursor protein (APP) (9, 10), integrins (11,12), and members of the LDL receptor family (13-17) ...

Although our understanding of adult neurogenesis has increased dramatically over the last decade, confusion still exists regarding both the identity of the stem cell responsible for neuron production and the mechanisms that regulate its activity. Here we show, using flow cytometry, that a small population of cells (0.3%) within the stem cell niche of the rat subventricular zone (SVZ) expresses the p75 neurotrophin receptor (p75 NTR ) and that these cells are responsible for neuron production in both newborn and adult animals. In the adult, the p75 NTR defines a discrete population of highly proliferative SVZ precursor cells that are able to respond to neurotrophin activation by increasing neuroblast generation, making this pathway the most likely mechanism for the increased neurogenesis that accompanies raised BDNF levels in a variety of disease and behavioral situations.

The cytoplasmic juxtamembrane region of the p75 neurotrophin receptor (p75 NTR ) has been found to be necessary and sufficient to initiate neural cell death. The region was named "Chopper" to distinguish it from CD95-like death domains. A 29-amino acid peptide corresponding to the Chopper region induced caspase-and calpain-mediated death in a variety of neural and nonneural cell types and was not inhibited by signaling through Trk (unlike killing by full-length p75 NTR ). Chopper triggered cell death only when bound to the plasma membrane by a lipid anchor, whereas non-anchored Chopper acted in a dominant-negative manner, blocking p75 NTR -mediated death both in vitro and in vivo. Removal of the ectodomain of p75 NTR increased the potency of Chopper activity, suggesting that it regulates the association of Chopper with downstream signaling proteins.The p75 neurotrophin receptor (p75 NTR

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Older age is associated with changes in the brain, including the medial temporal lobe, which may result in mild spatial navigation deficits, especially in allocentric navigation. The aim of the study was to characterize the profile of real-space allocentric (world-centered, hippocampus-dependent) and egocentric (body-centered, parietal lobe dependent) navigation and learning in young vs. older adults, and to assess a possible influence of gender. We recruited healthy participants without cognitive deficits on standard neuropsychological testing, white matter lesions or pronounced hippocampal atrophy: 24 young participants (18–26 years old) and 44 older participants stratified as participants 60–70 years old (n = 24) and participants 71–84 years old (n = 20). All underwent spatial navigation testing in the real-space human analog of the Morris Water Maze, which has the advantage of assessing separately allocentric and egocentric navigation and learning. Of the eight consecutive trials, trials 2–8 were used to reduce bias by a rebound effect (more dramatic changes in performance between trials 1 and 2 relative to subsequent trials). The participants who were 71–84 years old (p < 0.001), but not those 60–70 years old, showed deficits in allocentric navigation compared to the young participants. There were no differences in egocentric navigation. All three groups showed spatial learning effect (p’ s ≤ 0.01). There were no gender differences in spatial navigation and learning. Linear regression limited to older participants showed linear (β = 0.30, p = 0.045) and quadratic (β = 0.30, p = 0.046) effect of age on allocentric navigation. There was no effect of age on egocentric navigation. These results demonstrate that navigation deficits in older age may be limited to allocentric navigation, whereas egocentric navigation and learning may remain preserved. This specific pattern of spatial navigation impairment may help differentiate normal aging from prodromal Alzheimer’s disease.