Abstract
T-006, a small-molecule compound derived from tetramethylpyrazine (TMP), has potential for the treatment of neurological diseases. In order to investigate the effect of T-006 prophylactic treatment on an Alzheimer's disease (AD) model and identify the target of T-006, we intragastrically administered T-006 (3 mg/kg) to Alzheimer's disease (AD) transgenic mice (APP/PS1-2xTg and APP/PS1/Tau-3xTg) for 6 and 8 months, respectively. T-006 improved cognitive ability after long-term administration in two AD mouse models and targeted mitochondrial-related protein alpha-F1-ATP synthase (ATP5A). T-006 significantly reduced the expression of phosphorylated-tau, total tau, and APP while increasing the expression of synapse-associated proteins in 3xTg mice. In addition, T-006 modulated the JNK and mTOR-ULK1 pathways to reduce both p-tau and total tau levels. Our data suggested that T-006 mitigated cognitive decline primarily by reducing the p-tau and total tau levels in 3xTg mice, supporting further investigation into its development as a candidate drug for AD treatment.
Keywords:
APP; ATP5A; Alzheimer’s disease (AD); Tau; mTOR-ULK1.
MeSH terms
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Alzheimer Disease / drug therapy*
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Autophagy / drug effects
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Autophagy-Related Protein-1 Homolog / metabolism
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Avoidance Learning
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Cognition Disorders / drug therapy*
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Disease Models, Animal
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Donepezil / pharmacology
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Donepezil / therapeutic use
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Drug Evaluation, Preclinical
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Hydrazones / pharmacology
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Hydrazones / therapeutic use*
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MAP Kinase Signaling System / drug effects
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Memantine / pharmacology
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Memantine / therapeutic use
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Mice
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Mice, Transgenic
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Morris Water Maze Test
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use*
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Pyrazines / pharmacology
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Pyrazines / therapeutic use*
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Random Allocation
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Recognition, Psychology
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism
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tau Proteins / metabolism*
Substances
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Amyloid beta-Protein Precursor
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Hydrazones
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Mapt protein, mouse
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Neuroprotective Agents
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Pyrazines
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T-006 compound
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tau Proteins
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Donepezil
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mTOR protein, mouse
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Autophagy-Related Protein-1 Homolog
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TOR Serine-Threonine Kinases
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Ulk1 protein, mouse
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Memantine