Pancreas patch grafting to treat type 1 diabetes.

Stem/progenitor cell therapy is a promising treatment option for patients with type 1 diabetes (T1D) a disease characterized by autoimmune destruction of pancreatic ß cells. Actively injecting cells into an organ is one option for cell delivery, but in the pancreas, this contributes to acute inflammation and pancreatitis. We employed a patch grafting approach to transplant biliary tree stem cells/progenitor cells (BTSC) onto the surface of the pancreas in diabetic mice. The cells engraft and differentiate into ß-like cells reversing hyperglycemia during a four-month period of observation. In addition, C-peptide and insulin gradually increase in blood circulation without detectable adverse effects during this period. Moreover, the patch graft transplant promoted the proliferation and differentiation of pancreatic ß-like cells with co-expression of the ß cell biomarker. CONCLUSION: BTSC transplantation can effectively attenuate T1D over a four-month period that is vital important for clinical applications.

Suppression of HIV-associated Macrophage Activation by a p75 Neurotrophin Receptor Ligand.

Previous studies indicated that nerve growth factor (NGF) and proNGF differentially regulate the phenotype of macrophages and microglia via actions at tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptors (p75NTR), respectively. The ability of HIV gp120 and virions to induce the secretion of factors toxic to neurons was suppressed by NGF and enhanced by proNGF, suggesting the potential for neurotrophin based "anti-inflammatory" interventions. To investigate the "anti-inflammatory" potential of the p75NTR ligand, LM11A-31, we treated cultured macrophages and microglia with HIV gp120 in the presence or absence of the ligand and evaluated the morphological phenotype, intrinsic calcium signaling, neurotoxic activity and proteins in the secretome. LM11A-31 at 10 nM was able to suppress the release of neurotoxic factors from both monocyte-derived macrophages (MDM) and microglia. The protective effects correlated with a shift in morphology and a unique secretory phenotype rich in growth factors that overrode the actions of HIV gp120. The protein pattern was generally consistent with anti-inflammatory, phagocytic and tissue remodeling functions. Although the toxic factor(s) and the source of the neuroprotection were not identified, the data indicated that an increased degradation of NGF induced by HIV gp120 was likely to contribute to neuronal vulnerability. Although substantial work is still needed to reveal the functions of many proteins in the mononuclear phagocyte secretome, such as growth and differentiation factors, the data clearly indicate that the ligand LM11A-31 has excellent therapeutic potential due to its ability to induce a more protective phenotype that restricts activation by HIV.

Modulation of the p75 neurotrophin receptor suppresses age-related basal forebrain cholinergic neuron degeneration.

Age-related degeneration of basal forebrain cholinergic neurons (BFCNs) is linked to cognitive impairment. The p75 neurotrophin receptor (p75NTR) has been proposed to mediate neuronal degeneration in aging. Therefore, we tested the hypothesis that modifying p75NTR function would prevent or reverse aging-related neuronal degeneration using LM11A-31, a small molecule p75NTR modulator that downregulates degenerative and upregulates trophic receptor-associated signaling. Morphological analysis in mice showed loss of BFCN area detectable by 18 months of age. Oral administration of LM11A-31 from age 15 to 18 months resulted in a dose-related preservation of BFCN area and one month of treatment from 17 to 18 months also preserved cell area. To evaluate reversal of established neuronal atrophy, animals were treated from 21 to 25 months of age. Treatment was associated with an increase of cell size to a mean area larger than that observed at 18 months, accompanied by increases in mean MS/VDB neurite length, as well as increased cholinergic fiber density and synaptophysin pre-synaptic marker levels in the hippocampus. These findings support the idea that modulation of p75NTR activity can prevent and potentially reverse age-associated BFCN degeneration. Moreover, this may be achieved therapeutically with orally bioavailable agents such as LM11A-31.

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants.

Many chemotherapy drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. In the present study, we examine the effects of paclitaxel (taxol), cisplatin, and methotrexate on primary rat neurons including hippocampal, cortical, and dorsal horn/dorsal root ganglion neuronal cultures. We found that all of these anti-cancer drugs induce substantial neurotoxicity evidenced by neurite degeneration. The neurons are capable of recovering after treatment withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn. After cisplatin and methotrexate treatment, we observed the degeneration of neuronal processes including the reduction of dendritic branching, length, and altered growth cone formation, indicating an abnormal arrangement of the actin cytoskeleton consistent with the involvement of Rho family small GTPases. Inhibiting RhoA downstream effector p160 ROCK/Rho kinase using Y-27632, or activating p75 neurotrophin receptor (p75 NTR) using non-peptide mimetic LM11A-31, were able to reverse the degeneration caused by cisplatin and methotrexate. Therefore, the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway.

Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death.

Studies showing that neurotrophin binding to p75NTR can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75NTR in a monovalent manner, raise the possibility that small molecule p75NTR ligands that positively regulate survival might be found. A pharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75NTR was applied to in silico screening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75NTR. In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75NTR-dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75NTR behaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.

Small molecule neurotrophin receptor ligands: novel strategies for targeting Alzheimer's disease mechanisms.

A number of factors limit the therapeutic application of neurotrophin proteins, such as nerve growth factor (NGF) and brain-derived growth factor (BDNF), for Alzheimer's and other neurodegenerative diseases. These factors include unfavorable pharmacological properties typical of proteins and the pleiotropic effects mediated by protein-ligand interactions with p75(NTR), Trk, and sortilin neurotrophin receptors. Targeted modulation of p75(NTR) provides a strategy for preventing degeneration without promoting TrkA-mediated deleterious effects, and targeted activation of TrkB might achieve more favorable neurotrophic effects than those achieved by concomitant activation of p75(NTR) and TrkB. The discovery of small molecules functioning as ligands at specific neurotrophin receptors has made possible for the first time approaches for modulating selected components of neurotrophin signaling processes for the purpose of modulating underlying Alzheimer's disease mechanisms.

[Carrier genetic diagnosis of intron and/or exon-deletion Duchenne muscular dystrophy by microsatellite analysis and quantitative polymerase chain reaction].

OBJECTIVE: To detect the female carriers from the intron and/or exon-deletion Duchenne/Becker musclular dystrophy (DMD) familial members for prenatal or preimplantation genetic diagnosis. METHODS: Using method of PCR to five microsatellite markers (located in 5' terminus and intron 44, 45, 49, 50), analysing of the short tandem repeat sequence polymorphism with the genescan and binding with the quantitative polymerase chain reaction, we detected the DMD carriers from 1 intron and exon -deletion family and 1 intron-deletion family. RESULTS: The STR-50 genotype of II 2 in family 5 was 245/245, so II3 is DMD gene carrier. The STR-45 genotype of II6 and II8 were del/172, III19 was del/178, so they were all DMD gene carriers. CONCLUSION: The STR haploid linkage analysis combined with quantitative polymerase chain reaction is accurate and efficient to detect the female carriers from the intron and/or exon-deletion DMD familial members.

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology.

The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.

Small molecule approaches for promoting neurogenesis.

The discovery of small molecules capable of promoting neurogenesis will contribute to the elucidation of the physiological roles of neurogenesis and to novel therapeutic approaches. Small molecule development can be targeted to the promotion of precursor proliferation, survival, migration or maturation and might be applied to augmenting physiological neurogenesis already present in the dentate gyrus or subventricular zone/olfactory bulb or to normally non-neurogenic regions relevant to neuropathological states. Current small molecule discovery can be assessed from the perspective of the following categories: compounds modulating physiological signaling pathways regulating neurogenesis including the sonic hedgehog, bone morphogenic protein Wnt/,-catenin, Notch and chemokine systems; growth factor mimetics; protein tyrosine phosphatase inhibitors; existing drugs including antidepressants, lithium, valproate, sildenafil and statins; hormones, steroids and peptides; and neurotransmitter receptor agonists and antagonists. Unbiased, high throughput screening will likely lead to the discovery of additional active compounds and the recognition of novel mechanisms regulating neurogenesis. A major therapeutic challenge will consist of the identification of molecular targets and mechanisms relatively specific for precursor cells of interest.

Leukocyte antigen-related protein tyrosine phosphatase receptor: a small ectodomain isoform functions as a homophilic ligand and promotes neurite outgrowth.

The identities of ligands interacting with protein tyrosine phosphatase (PTP) receptors to regulate neurite outgrowth remain mainly unknown. Analysis of cDNA and genomic clones encoding the rat leukocyte common antigen-related (LAR) PTP receptor predicted a small, approximately 11 kDa ectodomain isoform, designated LARFN5C, containing a novel N terminal followed by a C-terminal segment of the LAR fifth fibronectin type III domain. RT-PCR and Northern blot analysis confirmed the presence of LARFN5C transcripts in brain. Transfection of COS cells with LARFN5C-Fc cDNA resulted in expression of the predicted protein, and Western blot analysis verified expression of approximately 11 kDa LARFN5C protein in vivo and its developmental regulation. Beads coated with rLARFN5C demonstrated aggregation consistent with homophilic binding, and pull-down and immunoprecipitation assays demonstrated that rLARFN5C associates with the LAR receptor. rLARFN5C binding to COS cells was dependent on LAR expression, and rLARFN5C binding to LAR +/+ hippocampal neurons was fivefold greater than that found by using LAR-deficient (-/-) neurons. Substratum-bound rLARFN5C had potent neurite-promoting effects on LAR +/+ neurons, with a fivefold loss in potency with the use of LAR -/- neurons. rLARFN5C in solution at low nanomolar concentrations inhibited neurite outgrowth induced by substratum-bound rLARFN5C, consistent with receptor-based function. These studies suggest that a small ectodomain isoform of a PTP receptor can function as a ligand for the same receptor to promote neurite outgrowth.

[Therapy of Duchenne muscular dystrophy with umbilical cord blood stem cell transplantation].

OBJECTIVE: To analyze a Duchenne muscular dystrophy(DMD) patient's muscular regeneration, dystrophin expression and locomotive variation before and after he underwent umbilical cord blood stem cell transplantation in order to assess the therapeutic effect. METHODS: A 12-year-old DMD boy who could not walk for 3 years was confirmed by gene analysis and dystrophin protein immune test on his muscle. He had no other chronic disease. By HLA matching, a piece of umbilical cord blood stem cell with 6 HLA sites matching to the boy was found in Guangdong Umbilical Cord Blood Bank. The number of the nucleated cells of the umbilical cord blood stem cell was 24.08x 10(8). After pretreatment for the DMD boy with busulfan, cyclophosphamide and rabbit anti-human thymocyte globulin, the allergenic cord blood stem cells were transplanted into him by intravenous injection. Cyclosporin A, methylprednisolone, MMF, prostaglandin E1 and ganciclovir were given after the transplantation. At the same time, Gran, the granulocytic cell stimulating factor, and gamma globulin were administered. The biochemistry profile including serum creatine kinase (CK), the reconstruction of blood making, the deletion exon of DMD gene, the regenerating muscles, the dystrophin protein expression, and the locomotive function of the DMD boy were tested regularly. RESULTS: (1) The white blood cells (WBC) of peripheral blood decreased gradually to zero after pretreatment. In a period of 15 days after transplantation, the neutrophil increased to 0.5x 10(9)/L; at 25 days, WBC increased to normal level. Blood platelet was more than 20x 10(9)/L at 22 days. The hemoglobin rose to 85-100 g/L. At 140 days, sternal puncture revealed the rapid growth of neutrophil, blood platelet and hemoglobin. (2)At 140 days, the blood type of the DMD boy transformed from type O to type AB (the donor's blood type being AB). There was no grafe versus host reaction. (3) At 18, 30, 43, 55, 74 and 233 days after transplantation, the PCR-short tandem repeat test of the boy's peripheral blood DNA showed that his genotype was completely the same as the donor's. The results of PCR-short tandem repeat tests of the bone marrow cells DNA by sternal puncture at 140, 183 and 235 days were the same as those of the blood DNA. (4) At 60 days, DMD gene analysis by PCR showed that the defected DMD gene (exon 19 deletion) had been corrected by the umbilical cord stem cells transplantation. (5) At 75 days, the biopsy of calf muscle showed there were myoblast cells and muscular tubes growing. The dystrophin expressions were weak, but a few of them were strong. DNA analysis showed that the donor's gene DNA accounted for 1%-13%. At 126 days, obviously increased dystrophin positive muscular fibers of the boy were found. The donor's fibers rose to 2.5%-25%. (6) The serum CK of the boy declined from 5735 U/L to 274 U/L. (7) At 100 days, physical examination revealed improvement in his arms and legs. CONCLUSION: The therapy of Duchenne muscular dystrophy with allogeneic umbilical cord blood hematopoietic stem cell transplantation may reset up the blood-making function, decrease the serum CK level, restore the dystrophin in muscles, and improve the locomotive function of the DMD boy. These data suggest that the allogeneic umbilical cord blood hematopoietic stem cell transplantation may benefit the DMD boys.

Alzheimer's therapeutics: neurotrophin domain small molecule mimetics.

Factors limiting the therapeutic application of neurotrophins to neurodegenerative diseases include poor stability and CNS penetration. Moreover, certain neurotrophin effects, such as promotion of neuronal death via interaction with the p75NTR receptor, might further limit their application. We have proposed that development of small molecule mimetics of neurotrophins might serve to overcome these limitations. In previous work, our laboratory established the proof-of-principle that mimetics of specific nerve growth factor (NGF) domains could prevent neuronal death. Peptidomimetics of the loop 1 domain prevent death via p75NTR-dependent signaling and peptidomimetics of the loop 4 domain prevent death via Trk-related signaling. In current work we are designing pharmacophore queries corresponding to loop domains 1 or 4 that incorporate features of the NGF crystal structure along with features derived from peptidomimetic structure-activity-relationships. Screening of in silico databases containing non-peptide, small molecules has identified a number of candidate NGF domain mimetics. Preliminary assessment of these compounds using neurotrophin bioassays indicates that several are capable of preventing neuronal death. Ongoing studies will determine whether these compounds act via p75NTR or Trk receptors.

Alzheimer's therapeutics: neurotrophin small molecule mimetics.

A substantial portion of neuronal populations undergoing degeneration in Alzheimer's and other neurodegenerative disorders express neurotrophin receptors. Neurotrophin small molecule mimetics constitute candidate compounds that might be useful in preventing or delaying loss of neuronal function, neural networks or neuronal death in neurodegenerative states. We are testing the hypothesis that pharmacophores based on a combination of the crystal structures of neurotrophins and structure-activity relationships of active neurotrophin peptidomimetics can be used to screen small molecule libraries to identify non-peptide small molecules with neurotrophin agonist or antagonist activity. In preliminary screens using pharmacophores based on two nerve growth factor (NGF) loop domains, a number of small molecules have been identified that display neurotrophic activity using in vitro bioassays. Current studies are focused on determining whether these small molecules function via neurotrophin receptors and whether they activate neurotrophin signaling cascades. Assessment of structure-activity relationships between active and inactive small molecules will allow modification of pharmacophores and provide a basis for the iterative process if identifying compounds with increased potency and efficacy. A collection of such compounds will provide a basis for synthesis of compounds with targeted pharmacological properties.

A candidate chimeric mammalian mRNA transcript is derived from distinct chromosomes and is associated with nonconsensus splice junction motifs.

The process of creating chimeric mRNA transcripts derived from separately transcribed genes via known spliceosome mechanisms is termed trans-splicing, and has been primarily described in lower eukaryotes. Isolation of cDNA clones containing sequences from distinct genes has raised the possibility of trans-splicing across distinct genes in mammalian systems; however, the possibility of cloning artifacts or splicing via nonspliceosome mechanisms has been difficult to rule out. In most cases, the absence of corresponding genomic clones has limited assessment of splice donor and acceptance sites and associated intronic elements that would be expected to participate in spliceosome-based reactions. We have previously reported a cDNA clone encoding the rat Leukocyte Common Antigen-Related (LAR) tyrosine phosphatase receptor that contains an alternative 3' UTR. In the present study Northern, RT-PCR and RNase protection assays verified the existence of developmentally regulated 3' UTR alternative splicing of LAR transcripts in vivo. FISH and radiation hybrid mapping demonstrated that loci encoding LAR and its alternative 3' UTR are present on distinct chromosomes, raising the possibility that alternatively spliced transcripts resulted from trans-splicing. Exon/intron analysis of corresponding genomic clones revealed nonconsensus splice junctions along with elements known to promote both cis- and trans-splicing. Verification in a mammalian in vivo system of chimeric transcripts derived from distinct genes along with identification of atypical nonconsensus-associated genomic elements points to the novel possibilities of atypical spliceosome-based trans-splicing or nonconventional, nonspliceosome-based mechanisms leading to chimeric transcripts.

[Dystrophin detection by immunofluorescent technique for diagnosing muscular dystrophy].

OBJECTIVE: To establish a specific technique for diagnosing and classifying Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), facioscapulohumeral muscular dystrophy (FSHD) and neurologic dystrophy. METHODS: Forty-seven cases were detected by immunofluorescence technique for analyzing dystrophin located in skeletal muscle cell membrane with the use of mouse monoclonal antibodies, goat and rabbit polyclonal antibodies. RESULTS: The normal individuals showed ringed positive staining stripe around muscle fibers. Negative result of staining was seen in 16 DMD patients. Eleven BMD patients had discontinuous or a patchy positive staining pattern, and all of 10 FSHD and 10 neurological amyotrophic patients showed positive dystrophin staining. CONCLUSION: Detecting dystrophin in the skeletal muscle cell membrane of muscular patients is an efficient technique for diagnosing and classifying various types of muscular dystrophy.

[Carrier detection of Duchenne/Becker muscular dystrophy in Chinese families by microsatellite analysis].

OBJECTIVE: To screen and detect the female carriers from the DMD/BMD family members for prenatal or preimplantation genetic diagnosis. METHODS: For the detection of DMD/BMD carriers from 27 family members in 4 families, PCR to five microsatellite markers(located in 5' terminus and intron 44, 45, 49, 50) and analysis of the short tandem repeat(STR) sequence polymorphism with the use of genescan were implemented. RESULTS: Six of the 17 female members were obligate DMD gene carriers according to the haplotype analysis of the results of the genescan, which conformed with the pedigree analysis. Besides, the authors detected five carriers and five normal females in these families with the use of the haplotype analysis only. The most polymorphic locus was STR 49, and the least was STR 50. CONCLUSION: The STR haploid linkage analysis using (CA)n repeats within the human dystrophin gene is a rapid,accurate, objective method and is well suited for routine use in clinical laboratories engaged in DMD/BMD linkage analysis for the detection of carrier.

[Application of the Bgl II-Bln I dosage test to gene diagnosis of facioscapulohumeral muscular dystrophy 1A gene].

OBJECTIVE: To increase the sensitivity and specificity of conventional gene diagnosis of facioscapulohumeral muscular dystrophy 1A(FSHD1A) by analyzing the distribution of translocation between chromosomes 4q35 and 10q26 in suspected FSHD cases. METHODS: The Bgl II- Bln I dosage test was performed to detect translocation between chromosomes 4q35 and 10q26 in 7 cases of presymptomatic FSHD patients showing positive result in gene diagnosis and 5 cases of sporadic FSHD patients showing negative result in gene diagnosis. DNA samples were digested with Bgl II and Bln I, followed by agrose gel electrophoresis. Probe p13E-11 was labeled with alpha-(32) P dCTP, followed by Southern hybridization. Then the ratio between the chromosomes 4 and 10 derived signal intensities was judged and hence was made known whether there was interchromosomal translocation between chromosomes 4 and 10. RESULTS: The Bgl II-Bln I dosage test revealed a translocation from chromosome 4q35 to 10q26 in one presymptomatic FSHD patient, thus indicating the result of gene diagnosis for her might be false positive. There was one translocation from chromosome 10q26 to 4q35 detected in one sporadic FSHD patient, indicating the result of gene diagnosis for her might be false negative. There were no translocations between chromosomes 4 and 10 in the other 10 cases. CONCLUSION: The Bgl II-Bln I dosage test can detect the translocation between chromosomes 4q35 and 10q26. It can improve the accuracy of the conventional method for gene diagnosis of FSHD1A.

[Single cell analysis of some deletion in dystrophin gene exons and gender determination by 3-plex nested PCR].

OBJECTIVE: To set up a technique of single lymphocytes 3-plex nested PCR for dystrophin and SRY gene, and to evaluate the possibility of using this technique for preimplantation genetic diagnosis(PGD) of deleted Duchenne muscular dystrophy (DMD) with family history. METHODS: Fifty single lymphocytes of a normal male and fifty of a normal female were obtained for detecting dystrophin gene(exon 51, exon 19, exon 48) and SRY gene by 3-plex nested PCR. RESULTS: In the group of exon 51/exon 19/SRY, the amplification rates of exon 51, exon 19 and SRY in male were 96%, 94% and 94%; the amplification rates of exon 51 and exon19 in female were 94% and 94%, respectively. In the exon 48/exon 19/SRY group, the amplification rates of exon 48, exon 19 and SRY in male were 92%, 90% and 94%, the amplification rates of exon 48, exon 19 in female were 94% and 92%, respectively. CONCLUSION: The technique of single lymphocytes 3-plex nested PCR for dystrophin and SRY gene established in this study is highly sensitive, specific and reliable, and is suitable for PGD of deleted DMD with family history.

[Dystrophin and utrophin expression in muscle tissues of DMD mouse model after transplantation treatment by bone marrow mesenchymal stem cells].

OBJECTIVE: To observe dystrophin and utrophin expression in muscle tissues of Duchenne muscular dystrophy (DMD) mouse model (dko mouse) after having been treated with bone marrow mesenchymal stem cells (MSC) transplantation. METHODS: The fifth generation of MSCs, cultured in vitro, was transplanted into dko mice by tail vein. The fluorescent expression of dystrophin and utrophin in gastrocnemius muscle tissue of dko mouse was detected and the average optical density of positive fibers was calculated. RESULTS: MSCs that had been cultured for three generations had good homogeneousness and the immunological reaction after vein transplantation was low. There was an increasing tendency of dystrophin and utrophin fluorescent expression in sarcolemma of dko mouse within 5-20 weeks. Significant difference existed in fluorescent average optical density of positive fibers fifteen weeks before and after cell transplantation. CONCLUSIONS: MSC has strong plasticity both in vitro and in vivo. MSC has a trend to reach the injured muscle tissues and turn into muscle fibers, which express dystrophin and utrophin. There is some plerosis function for myatrophy of dko mouse by MSC transplantation.

Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model.

The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-ß-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.