Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Pathology
• Genetics

Background:

• Early Alzheimer's disease (AD) is characterized by navigation deficits and abnormal hyperphosphorylated tau (aTau) in the entorhinal cortex (EC).
• As AD progresses, aTau spreads to the subiculum (Sub), a region crucial for memory, leading to memory impairments.
• Understanding the neurophysiological impact of aTau spread from EC to Sub is vital for developing interventions.

Purpose of the Study:

• To investigate the effects of aTau progression from the EC to the Sub on neurophysiology and memory.
• To create a mouse model that mimics early AD pathology by seeding human mutant tau in Sub-projecting EC neurons.

Main Methods:

• A cre-dependent viral vector (AAV2/9-Flex-P301L-GFP) was used to selectively deposit mutant human tau in EC layer 2/3 neurons projecting to the Sub in a transgenic mouse line.
• Mice were allowed 4 weeks to 12 months for aTau expression before undergoing behavioral testing for spatial, temporal-association, and contextual memory, as well as anxiety.
• Performance was compared against cre-negative littermate controls without tau expression.

Main Results:

• The viral strategy successfully targeted Sub-projecting EC layer 2/3 neurons, confirmed by immunofluorescence for human tau (AT7) and phosphorylated tau (AT8).
• Mice with aTau in the EC-Sub circuit exhibited impaired trace memory (p=0.027) but retained intact spatial and contextual memory.
• No significant differences in anxiety levels were observed between the groups.

Conclusions:

• Selective delivery of human mutant tau to the EC-Sub circuit demonstrably impairs temporal-association memory.
• These findings support previous research linking circuit dysfunction to association memory deficits.
• This study provides a valuable model for investigating specific memory loss mechanisms and for testing strategies to slow aTau spread and restore memory function.