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Doxycycline counteracts neuroinflammation restoring memory in Alzheimer's disease mouse models
Claudia Balducci1, Giulia Santamaria1, Pietro La Vitola1
1Department of Neuroscience, IRCCS, Istituto di Ricerhe Farmacologiche Mario Negri, Milano, Italy.
Abstract:
β-Amyloid oligomers (AβOs) and neuroinflammation are 2 main culprits to counteract in Alzheimer's disease (AD). Doxycycline (DOXY) is a second generation antibiotic of the tetracycline class that are promising drugs tested in many clinical trials for a number of different pathologies. DOXY is endowed with antiamyloidogenic properties and better crosses the blood-brain barrier, but its efficacy has never been tested in AD mice. We herein show that 15- to 16-month-old APP/PS1dE9 (APP/PS1) AD mice receiving DOXY under different treatment regimens recovered their memory without plaque reduction. An acute DOXY treatment was, also, sufficient to improve APP/PS1 mouse memory, suggesting an action against soluble AβOs. This was confirmed in an AβO-induced mouse model, where the AβO-mediated memory impairment was abolished by a DOXY pretreatment. Although AβOs induce memory impairment through glial activation, assessing the anti-inflammatory action of DOXY, we found that in both the AβO-treated and APP/PS1 mice, the memory recovery was associated with a lower neuroinflammation. Our data promote DOXY as a hopeful repositioned drug counteracting crucial neuropathological AD targets.
Insights
Doxycycline (DOXY) improved memory in Alzheimer's disease (AD) mice by targeting soluble amyloid-beta oligomers (AβOs) and reducing neuroinflammation, without affecting plaque buildup.
Area of Science:
- Neuroscience
- Pharmacology
- Alzheimer's Disease Research
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta oligomers (AβOs) and neuroinflammation.
- Doxycycline (DOXY), a tetracycline antibiotic, shows potential due to its ability to cross the blood-brain barrier and possess antiamyloidogenic properties.
Purpose of the Study:
- To investigate the efficacy of doxycycline (DOXY) in ameliorating cognitive deficits in a mouse model of Alzheimer's disease (AD).
- To determine if DOXY's effects are linked to reductions in amyloid-beta oligomers (AβOs) or neuroinflammation.
Main Methods:
- Treatment of APP/PS1dE9 (APP/PS1) AD mice and wild-type mice with doxycycline (DOXY) under various regimens.
- Administration of AβOs to induce memory impairment in mice, followed by DOXY pretreatment.
- Assessment of memory recovery and neuroinflammation markers.
Main Results:
- Doxycycline (DOXY) treatment led to memory recovery in APP/PS1 AD mice without reducing amyloid plaque load.
- Acute DOXY administration and pretreatment in an AβO-induced memory impairment model abolished cognitive deficits.
- Memory recovery in both models was correlated with reduced neuroinflammation.
Conclusions:
- Doxycycline (DOXY) effectively counteracts soluble AβOs and reduces neuroinflammation, improving memory in AD mouse models.
- DOXY shows promise as a repositioned therapeutic agent for Alzheimer's disease (AD).