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1.  Small Molecule p75NTR Ligands Reduce Pathological Phosphorylation and Misfolding of Tau, Inflammatory Changes, Cholinergic Degeneration, and Cognitive Deficits in AβPPL/S Transgenic Mice 
The p75 neurotrophin receptor (p75NTR ) is involved in degenerative mechanisms related to Alzheimer’s disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.
PMCID: PMC4278429  PMID: 24898660
Alzheimer’s disease; LM11A-31; LM11A-24; p75 neurotrophin receptor
2.  Thy1-hAPPLond/Swe+ mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function 
Brain and Behavior  2012;2(2):142-154.
Alzheimer's disease (AD), the most common form of dementia, is an age-dependent progressive neurodegenerative disorder. β-amyloid, a metabolic product of the amyloid precursor protein (APP), plays an important role in the pathogenesis of AD. The Thy1-hAPPLond/Swe+ (line 41) transgenic mouse overexpresses human APP751 and contains the London (V717I) and Swedish (K670M/N671L) mutations. Here, we used a battery of behavioral tests to evaluate general activity, cognition, and social behavior in six-month-old male Thy1-hAPPLond/Swe+ mice. We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior. In fear conditioning (FC), Thy1-hAPPLond/Swe+ mice did not display deficits in acquisition or in memory retrieval in novel context of tone-cued FC, but they showed significant memory retrieval impairment during contextual testing in an identical environment. Surprisingly, in a standard hidden platform water maze, no significant deficit was detected in mutant mice. However, a delayed-matching-to-place paradigm revealed a significant deficit in Thy1-hAPPLond/Swe+ mice. Lastly, in the social novelty session of a three-chamber test, Thy1-hAPPLond/Swe+ mice exhibited a significantly decreased interest in a novel versus a familiar stranger compared to control mice. This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients. In conclusion, the Thy1-hAPPLond/Swe+ mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.
PMCID: PMC3345358  PMID: 22574282
Alzheimer's disease; amyloid precursor protein; behavior; learning and memory; neurodegenerative disorder; social interaction
3.  Androgens selectively protect against apoptosis in hippocampal neurones 
Journal of neuroendocrinology  2010;22(9):1013-1022.
Androgens can protect neurones from injury, but androgen neuroprotection is not well characterised in terms of either specificity or mechanism. Here, we compared the ability of androgens to protect neurones against a panel of insults, empirically determined to induce cell death by apoptotic or non-apoptotic mechanisms. Three criteria defining, but not inclusive of apoptosis are: protection by caspase inhibition, protection by protein synthesis inhibition, and presence of pyknotic nuclei. According to these criteria, β-amyloid, staurosporine, and Apoptosis Activator II induced cell death involving apoptosis, while hydrogen peroxide (H2O2), iron, calcium ionophore, and 3-nitropropionic acid induced cell death featuring non-apoptotic characteristics. Pretreatment of hippocampal neurones with testosterone or dihydrotestosterone attenuated cell death induced by β-amyloid, staurosporine, and Apoptosis Activator II, but none of the other insults. The anti-oxidant Trolox did not reduce cell death induced by β-amyloid, staurosporine, and Apoptosis Activator II, but did protect against H2O2 and iron. Similarly, a supra-physiological concentration of oestrogen reduced cell death induced by H2O2 and iron, an effect not observed with androgens. We also show that activation of oestrogen pathways was not necessary for androgen neuroprotection. These data suggest that androgens directly activate a neuroprotective mechanism specific to inhibition of cell death involving apoptosis. Determining the specificity of androgen neuroprotection may enable the development of androgen compounds for the treatment of neurodegenerative disorders.
PMCID: PMC2924915  PMID: 20561156
Androgens; apoptosis; dihydrotestosterone; neuroprotection; oestrogen; testosterone
Brain research  2009;1298:1-12.
Although androgens induce numerous actions in brain, relatively little is known about which cell signaling pathways androgens activate in neurons. Recent work in our laboratory showed that the androgens testosterone and dihydrotestosterone (DHT) activate androgen receptor (AR)-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling. Since the transcription factor cyclic AMP response element binding protein (CREB) is a downstream effector of MAPK/ERK and androgens activate and CREB in non-neuronal cells, we investigated whether androgens activate CREB signaling in neurons. First, we observed that DHT rapidly activates CREB in cultured hippocampal neurons, as evidenced by CREB phosphorylation. Further, we observed that DHT-induced CREB phosphorylation is AR-dependent, as it occurs in PC12 cells stably transfected with AR but in neither wild-type nor empty vector-transfected cells. Next, we sought to identify the signal transduction pathways upstream of CREB phosphorylation using pharmacological inhibitors. DHT-induced CREB phosphorylation in neurons was found to be dependent upon protein kinase C (PKC) signaling but independent of MAPK/ERK, phosphatidylinositol 3-kinase, protein kinase A, and Ca2+/calmodulin-dependent protein kinase IV. These results demonstrate that DHT induces PKC-dependent CREB signaling, which may contribute to androgen-mediated neural functions.
PMCID: PMC2775803  PMID: 19729001
Androgen receptor; dihydrotestosterone; protein kinase C; signal transduction; testosterone
5.  The p75 neurotrophin receptor promotes Aβ-induced neuritic dystrophy in vitro and in vivo 
Oligomeric forms of amyloid-β(1–42) (Aβ) are thought to play a causal role in Alzheimer’s disease (AD) and the p75 neurotrophin receptor (p75NTR) has been implicated in Aβ-induced neurodegeneration. To further define the functions of p75NTR in AD, we examined the interaction of oligomeric Aβ with p75NTR, and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Aβ, and fluorescence resonance energy transfer (FRET) analysis revealed that Aβ oligomers interact with the extracellular domain of p75NTR. In vitro studies of Aβ-induced death in neuron cultures isolated from wildtype and p75NTR −/− mice, in which the p75NTR extracellular domain is deleted, showed reduced sensitivity of mutant cells to Aβ-induced cell death. Interestingly, Aβ-induced neuritic dystrophy and activation of c-Jun, a known mediator of Aβ-induced deleterious signaling, were completely prevented in p75NTR −/− neuron cultures. Thy1-hAPPLond/Swe X p75NTR−/− mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild type p75NTR. Aβ levels were not affected, suggesting that removal of p75NTR extracellular domain reduced the ability of excess Aβ to promote neuritic degeneration. These findings indicate that while p75NTR likely does not mediate all Aβ effects, it does play a significant role in enabling Aβ-induced neurodegeneration in vitro and in vivo, establishing p75NTR as an important therapeutic target for AD.
PMCID: PMC2771439  PMID: 19710315
p75NTR; amyloid-β; Alzheimer’s disease; neuritic dystrophy; neurodegeneration; basal forebrain cholinergic neurons
6.  Androgen cell signaling pathways involved in neuroprotective actions 
Hormones and behavior  2007;53(5):693-705.
As a normal consequence of aging in men, testosterone levels significantly decline in both serum and brain. Age-related testosterone depletion results in increased risk of dysfunction and disease in androgen-responsive tissues, including brain. Recent evidence indicates that one deleterious effect of age-related testosterone loss in men is increased risk for Alzheimer's disease (AD). We discuss recent findings from our laboratory and others that identify androgen actions implicated in protecting the brain against neurodegenerative diseases and begin to define androgen cell signaling pathways that underlie these protective effects. Specifically, we focus on the roles of androgens as (1) endogenous negative regulators of β-amyloid accumulation, a key event in AD pathogenesis, and (2) neuroprotective factors that utilize rapid non-genomic signaling to inhibit neuronal apoptosis. Continued elucidation of cell signaling pathways that contribute to protective actions of androgens should facilitate the development of targeted therapeutic strategies to combat AD and other age-related neurodegenerative diseases.
PMCID: PMC2424283  PMID: 18222446
androgen; testosterone; Alzheimer's disease; neuroprotection; β-amyloid; cell signaling
7.  Signal transduction in Alzheimer disease 
Journal of neurochemistry  2007;104(4):1065-1080.
The deficits in Alzheimer disease (AD) stem at least partly from neurotoxic β-amyloid peptides generated from the amyloid precursor protein (APP). APP may also be cleaved intracellularly at Asp664 to yield a second neurotoxic peptide, C31. Previously, we showed that cleavage of APP at the C-terminus is required for the impairments seen in APP transgenic mice, by comparing elements of the disease in animals modeling AD, with (platelet-derived growth factor B-chain promoter-driven APP transgenic mice; PDAPP) versus without (PDAPP D664A) a functional Asp664 caspase cleavage site. However, the signaling mechanism(s) by which Asp664 contributes to these deficits remains to be elucidated. In this study, we identify a kinase protein, recently shown to bind APP at the C-terminus and to contribute to AD, whose activity is modified in PDAPP mice, but normalized in PDAPP D664A mice. Specifically, we observed a significant increase in nuclear p21-activated kinase (isoforms 1, 2, and or 3; PAK-1/2/3) activation in hippocampus of 3 month old PDAPP mice compared with non-transgenic littermates, an effect completely prevented in PDAPP D664A mice. In contrast, 13 month old PDAPP mice displayed a significant decrease in PAK-1/2/3 activity, which was once again absent in PDAPP D664A mice. Similarly, in hippocampus of early and severe AD subjects, there was a progressive and subcellular-specific reduction in active PAK-1/2/3 compared with normal controls. Interestingly, total PAK-1/2/3 protein was increased in early AD subjects, but declined in moderate AD and declined further, to significantly below that of control levels, in severe AD. These findings are compatible with previous suggestions that PAK may be involved in the pathophysiology of AD, and demonstrate that both early activation and late inactivation in the murine AD model require the cleavage of APP at Asp664.
PMCID: PMC2553705  PMID: 17986220
C31; familial Alzheimer disease; intracellular domain; signal transduction; transgenic mouse model; β-amyloid precursor protein

Results 1-7 (7)