Cholinesterase inhibitors improve both memory and complex learning in aged beagle dogs

Area of Science:

• Neuroscience
• Comparative Medicine
• Pharmacology

Background:

• Aged dogs share key features with Alzheimer's disease (AD), including cognitive decline, amyloid-beta (Aβ) pathology, and cholinergic system deficits.
• Cholinergic hypofunction is implicated in age-related cognitive impairment in both humans and canines.

Purpose of the Study:

• To investigate the role of cholinergic hypofunction in aged dogs.
• To evaluate the efficacy of cholinesterase inhibitors phenserine and donepezil in improving cognitive function in a canine model of aging.
• To provide pharmacological validation for the aged dog as a model for Alzheimer's disease research.

Main Methods:

• Aged dogs were tested on a delayed non-matching-to-position task (DNMP) for working memory and an oddity discrimination task for complex learning.
• The effects of phenserine (0.5 mg/kg) and three doses of donepezil (0.75, 1.5, 6 mg/kg) were assessed on cognitive task performance.
• Scopolamine-induced deficits were used to partially assess the therapeutic effects of phenserine.

Main Results:

• Phenserine significantly improved DNMP performance at the longest delay and partially reversed scopolamine-induced deficits.
• Phenserine enhanced learning in a difficult oddity discrimination task but not an easier version.
• Donepezil (1.5 mg/kg) improved DNMP performance at the longest delay, indicating memory enhancement.

Conclusions:

• These findings further support the presence of cholinergic hypofunction in aged dogs.
• Phenserine and donepezil demonstrate therapeutic potential, validating the canine model for Alzheimer's disease (AD) drug screening.
• The aged dog serves as a valuable model for studying the interplay of cholinergic function, Aβ pathology, and cognitive decline in AD.