Detection of age-dependent working memory deterioration in APP751SL mice

Area of Science:

• Neuroscience
• Alzheimer's Disease Research
• Cognitive Impairment

Background:

• Clinical diagnosis of Alzheimer's disease (AD) relies on detecting cognitive decline, particularly memory impairments.
• Episodic and working memory deficits are key indicators of progression from mild cognitive impairment to AD.
• Current transgenic mouse models of AD often fail to exhibit early working memory deficits due to limitations in behavioral testing.

Purpose of the Study:

• To assess the early occurrence of working memory impairments in APP(751SL) transgenic mice.
• To develop a novel behavioral task to accurately measure working memory in AD models.
• To investigate the relationship between working memory deficits and amyloid-beta (Aβ) accumulation in the brain.

Main Methods:

• A new delayed matching-to-place task was designed and implemented in a water-maze to assess spatial recognition across four platform locations.
• Lesion studies in C57Bl6 mice (dorsal hippocampus vs. medial prefrontal cortex) were conducted to validate the task's sensitivity to memory deficits.
• APP(751SL) mice of different ages (5-6 months and 7-8 months) were tested using the novel water-maze task.
• Brain tissue was analyzed to correlate memory performance with Aβ accumulation in specific brain regions.

Main Results:

• Lesions of the dorsal hippocampus, but not the medial prefrontal cortex, induced time-dependent spatial recognition impairments in C57Bl6 mice.
• APP(751SL) mice aged 7-8 months exhibited working memory deficits comparable to those seen after hippocampal lesions.
• Younger APP(751SL) mice (5-6 months) did not show significant working memory impairments.
• The observed working memory deficits in older APP(751SL) mice correlated with progressive Aβ accumulation specifically in the hippocampus.

Conclusions:

• The novel water-maze task effectively detects early working memory deficits relevant to Alzheimer's disease progression.
• APP(751SL) mice develop hippocampal-dependent working memory impairments around 7-8 months of age.
• These deficits are associated with early-stage Aβ pathology in the hippocampus, offering a potential biomarker for early AD detection in preclinical models.