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Stereotactic Injection of MicroRNA-expressing Lentiviruses to the Mouse Hippocampus CA1 Region and Assessment of the Behavioral Outcome
Published on: June 10, 2013
Systemic delivery of liposome-loaded microRNA-195 ameliorates spatial memory impairment in a rat model of chronic
Xuqiao Wang1, Dongyang Wang1, Jiaqi Liu1
1Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, SKLFZCD; the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, Heilong Jiang Province, 150081, China.
Abstract:
Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular dementia (VaD), including amyloid-β (Aβ) deposition, tau phosphorylation, microglial activation and neural circuit dysfunction. Developing multitarget therapeutics to effectively prevent the transition from MCI to AD and/or VaD remains an urgent challenge. Herein, we engineered a brain-targeted dual-modified PEGylated nanoliposome (LipTM@miR-195), incorporating mannose (MAN) and the trans-activating protein of HIV type 1 (TAT), which encapsulates polyethyleneimine (PEI) complesed microRNA-195 (miR-195). In a CCH rat model, tail-vein administration of LipTM@miR-195 (0.112 mg/kg) efficiently crossed the blood-brain barrier (BBB) without detectable side effects. Treatment reversed CCH-induced spatial learning and memory deficits, rescued neural circuit dysfunction, and suppressed elevated APP, BACE1, AT8 and CD68 levels. Collectively, these findings provide compelling evidence that LipTM@miR-195 nanoliposome holds therapeutic potential for CCH-induced cognitive impairment, thereby preventing the progression from MCI to AD and/or VaD.
Insights
A novel nanoliposome therapy effectively treats chronic cerebral hypoperfusion (CCH) and cognitive deficits in rats. This breakthrough offers potential to prevent mild cognitive impairment (MCI) progression to Alzheimer's disease (AD) and vascular dementia (VaD).
Area of Science:
- Neuroscience
- Biotechnology
- Pharmacology
Background:
- Chronic cerebral hypoperfusion (CCH) is a preclinical stage of mild cognitive impairment (MCI), linked to Alzheimer's disease (AD) and vascular dementia (VaD).
- CCH causes brain pathology, including amyloid-beta deposition, tau phosphorylation, and neural circuit dysfunction.
- Effective multitarget therapeutics are needed to halt MCI progression to AD/VaD.
Purpose of the Study:
- To engineer and evaluate a brain-targeted nanoliposome (LipTM@miR-195) for treating CCH-induced cognitive impairment.
- To assess the therapeutic efficacy of LipTM@miR-195 in a rat model of CCH.
Main Methods:
- Developed dual-modified PEGylated nanoliposomes (LipTM@miR-195) encapsulating microRNA-195 (miR-195).
- Utilized mannose (MAN) and HIV-1 trans-activating protein (TAT) for brain targeting and polyethyleneimine (PEI) for miR-195 complexation.
- Administered LipTM@miR-195 intravenously in a CCH rat model and evaluated cognitive function, neural circuit activity, and key pathological markers.
Main Results:
- LipTM@miR-195 efficiently crossed the blood-brain barrier (BBB) in CCH rats with no observed side effects.
- Treatment reversed spatial learning and memory deficits induced by CCH.
- Suppressed CCH-associated increases in amyloid precursor protein (APP), BACE1, AT8 (phosphorylated tau), and CD68 (microglial activation) levels.
Conclusions:
- The engineered LipTM@miR-195 nanoliposome demonstrates significant therapeutic potential for CCH-induced cognitive impairment.
- This therapy may serve as a preventative strategy against the progression from MCI to AD and VaD.
- Targeted nanoliposome delivery of miR-195 offers a promising approach for neurodegenerative disease treatment.
