SLOH, a carbazole-based fluorophore, mitigates neuropathology and behavioral impairment in the triple-transgenic mouse model of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative dysfunction characterized by memory impairment and brings a heavy burden to old people both in developing and developed countries. Amyloid hypothesis reveals that aggregation and deposition of amyloid plaques are the cause of AD neurodegeneration. SLOH, a carbazole-based fluorophore, is reported to inhibit amyloid beta (Aβ) aggregation in vitro. In the current study, we intended to evaluate the protective effect of SLOH in a triple transgenic AD mouse model (3xTg-AD). 3xTg-AD (10-month-old) were treated with SLOH (0.5, 1 and 2 mg kg-1) for one month via intraperitoneal injection. After treatment, cognitive function was assessed by Morris Water Maze (MWM) and Y-maze tasks. In addition, biochemical estimations were used to examine the degree of Aβ deposition, tau hyperphosphorylation and neuroinflammation in the brains of 3xTg-AD mice. An in vitro study was conducted on human neuroblastoma (SH-SY5Y) cells to determine the activity of SLOH on tau and GSK-3β using western blot and immunofluorescence staining. One month treatment with SLOH significantly ameliorated memory impairments in 3xTg-AD mice in MWM and Y-maze tests. Moreover, SLOH treatment mitigated the level of amyloid plaques, tau hyperphosphorylation and neuroinflammation in the mouse brain. SLOH also reduced tau hyperphosphorylation and down-regulated GSK-3β activity in Aβ induced neurotoxic SH-SY5Y cells. The promising results in mitigating amyloid plaques, tau hyperphosphorylation, neuroinflammation and ameliorating cognitive deficits following one-month treatment suggest that SLOH could be a potential multi-target molecule for the AD treatment.

• Authors: Xiaoli Wu, Jayasankar Kosaraju, Wei Zhou, Kin Yip Tam
• Journal: Neuropharmacology (Neuropharmacology) Vol. 131 Pg. 351-363 (03 15 2018) ISSN: 1873-7064 [Electronic] England
• PMID: 29309769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Carbazoles
• MAPT protein, human
• Mapt protein, mouse
• Neuroprotective Agents
• Nootropic Agents
• tau Proteins
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse

Topics

• Alzheimer Disease (drug therapy, metabolism, pathology)
• Amyloid beta-Peptides (genetics, metabolism)
• Animals
• Brain (drug effects, metabolism, pathology)
• Carbazoles (pharmacology)
• Cell Line, Tumor
• Cognitive Dysfunction (drug therapy, metabolism, pathology)
• Dose-Response Relationship, Drug
• Female
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Inflammation (drug therapy, metabolism, pathology)
• Maze Learning (drug effects, physiology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Molecular Structure
• Neuroprotective Agents (pharmacology)
• Nootropic Agents (pharmacology)
• Random Allocation
• tau Proteins (genetics, metabolism)