Impairment of brain function in a mouse model of Alzheimer's disease during the pre-depositing phase: the role of alpha7 nicotinic acetylcholine receptors
Alzheimer's disease (AD) is an age-dependent incurable neurodegenerative disorder accompanied by neuroinflammation, amyloid accumulation and memory impairment. It begins decades before the first clinical symptoms appear, and identifying early biomarkers is key for developing disease-modifying therapies. We show now in a mouse model of AD that before any amyloid deposition the brains of 1.5-month-old mice contain increased levels of pro-inflammatory cytokines IL-1beta and IL-6, decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain and brain mitochondria and increased amounts of alpha7 nAChR-bound Abeta1-42, along with impaired episodic memory and increased risk of apoptosis. Both acute (1-week-long) and chronic (4-month-long) treatments with alpha7-selective agonist PNU282987, starting at 1.5 months of age, were well tolerated. The acute treatment did not affect the levels of soluble Abeta1-42 but consistently upregulated the alpha7 nAChR expression, decreased the level of alpha7-Abeta1-42 complexes and improved episodic memory of 1.5-month-old mice. The chronic treatment, covering the disease development phase, strongly upregulated the expression of all abundant brain nAChRs, reduced both free and alpha7-coupled Abeta1-42 within the brain, had anti-inflammatory and antiapoptotic effects, and potently upregulated cognition, thus identifying alpha7 nAChRs as both early biomarker and potent therapeutic target for fighting this devastating disease.