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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation
Eri Himeno1, Yasumasa Ohyagi, Linqing Ma
1Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Objective:
Intracellular amyloid β-protein (Aβ) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied.
Methods:
The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APP(KM670/671NL) /PS1(M146V)) and a tau gene mutation (Tau(P301L)). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Aβ degradation, activity of Aβ-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells.
Results:
After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Aβ, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aβ, increased activity of proteasome and insulin-degrading enzyme, protected against H(2) O(2) toxicity, and decreased p53 protein levels in the cultured cells.
Interpretation:
3xTg-AD mice show intraneuronal Aβ accumulation and memory disturbances before extracellular Aβ deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aβ and p-tau levels by APO treatment strongly suggest that intraneuronal Aβ is an important therapeutic target and APO will be a novel drug for AD.
Insights
Apomorphine (APO) significantly improved memory in an Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Intracellular amyloid-beta (Aβ) accumulation drives neurodegeneration in Alzheimer's disease (AD).
- Apomorphine (APO), a dopamine agonist, exhibits neuroprotective properties against oxidative stress.
Purpose of the Study:
- To investigate the efficacy of Apomorphine (APO) in a triple transgenic Alzheimer's disease (AD) mouse model.
- To elucidate the effects of APO on intracellular Aβ degradation and oxidative stress in neuronal cell cultures.
Main Methods:
- Treatment of 6-month-old 3xTg-AD mice with APO via subcutaneous injections for one month.
- Assessment of memory function using the Morris water maze test.
- Analysis of brain tissue via immunohistochemistry and Western blotting; evaluation of APO's effects on Aβ degradation, enzyme activity, and oxidative stress in SH-SY5Y cells.
Main Results:
- APO treatment led to significant improvements in short-term memory function in 3xTg-AD mice.
- Reduced levels of intraneuronal Aβ, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 were observed post-APO treatment.
- In cell cultures, APO enhanced intracellular Aβ degradation, increased proteasome and insulin-degrading enzyme activity, and provided protection against oxidative stress.
Conclusions:
- Intracellular Aβ accumulation and memory deficits precede extracellular Aβ deposition in the 3xTg-AD model.
- APO treatment improved memory and reduced key AD pathology markers (intraneuronal Aβ, p-tau), highlighting intracellular Aβ as a critical therapeutic target.
- Apomorphine (APO) shows promise as a novel therapeutic agent for Alzheimer's disease (AD).
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