title: Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AβPP(L/S) transgenic mice.
abstract: 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.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Thuy-Vi V
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Lilith
authors.initials: L
authors.lastname: Vander Griend
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Quach
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Belichenko
authors.affiliation: Department of Neurosurgery, Stanford University, Palo Alto, CA, USA.
authors.forename: Nay
authors.initials: N
authors.lastname: Saw
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Stanford University, Palo Alto, CA, USA.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA Palo Alto Veterans Affairs Health Care System, Palo Alto, CA, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Department of Veterans Affairs Medical Center, San Francisco, CA, USA Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000473:pathology*; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects*; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002795:Choline O-Acetyltransferase; D005904:Glial Fibrillary Acidic Protein; D007532:Isoleucine; D009025:Morpholines; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D016875:tau Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C575077:LM11A-31; C484065:NGFR protein, human
keywords: Alzheimer's disease; LM11A-24; LM11A-31; p75 neurotrophin receptor