A novel process driving Alzheimer's disease validated in a mouse model: Therapeutic potential

TY - JOUR

T1 - A novel process driving Alzheimer's disease validated in a mouse model

T2 - Therapeutic potential

AU - Greenfield, Susan A

AU - Cole, Gregory M

AU - Coen, Clive W

AU - Frautschy, Sally

AU - Singh, Ram P

AU - Mekkittikul, Marisa

AU - Garcia-Ratés, Sara

AU - Morrill, Paul

AU - Hollings, Owen

AU - Passmore, Matt

AU - Hasan, Sibah

AU - Carty, Nikisha

AU - Bison, Silvia

AU - Piccoli, Laura

AU - Carletti, Renzo

AU - Tacconi, Stephano

AU - Chalidou, Anna

AU - Pedercini, Matthew

AU - Kroecher, Tim

AU - Astner, Hubert

AU - Gerrard, Philip A

N1 - © 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.

PY - 2022/3/3

Y1 - 2022/3/3

N2 - Introduction: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood.Methods: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts-AD and a transgenic mouse model-to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology.Results: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques. NBP14 is a cyclized version of T14, which dose-dependently displaces binding of its linear counterpart to alpha-7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild-types.Discussion: These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential.

AB - Introduction: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood.Methods: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts-AD and a transgenic mouse model-to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology.Results: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques. NBP14 is a cyclized version of T14, which dose-dependently displaces binding of its linear counterpart to alpha-7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild-types.Discussion: These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential.

KW - 5XFAD, acetylcholinesterase, alphaLISA,Alzheimer’s disease,amyloid beta, basal forebrain, Braak stage, cortex, hippocampus, NBP14, novel object recognition, T14

U2 - 10.1002/trc2.12274

DO - 10.1002/trc2.12274

M3 - Article

C2 - 35415206

SN - 2352-8737

VL - 8

SP - e12274

JO - Alzheimer’s & Dementia: Translational Research & Clinical Interventions

JF - Alzheimer’s & Dementia: Translational Research & Clinical Interventions

IS - 1

ER -