Dopamine Loss Emerges as Key Driver of Memory Decline in Alzheimer’s

New research using APP-KI mice reveals that reduced dopamine signaling contributes significantly to memory decline in Alzheimer's disease, highlighting a previously underrecognized pathway alongside amyloid-β accumulation. Young APP-KI mice aged 3-6 months showed 78.6% correct trials for new odor associations versus 90.6% in wild-type mice, with performance declining further in older mice to 67.9% versus 84.9%. The study found that lateral entorhinal cortex layer 2/3 neurons, controlled by dopamine inputs from the ventral tegmental area and substantia nigra pars compacta, are critical for forming new associative memories but not retrieving existing ones. Researchers recorded 846 neurons from young APP-KI mice showing altered firing patterns and increased cue responses compared to wild-type controls. The findings align with fMRI studies showing the lateral entorhinal cortex suffers the earliest activity loss in Alzheimer's patients, potentially offering new therapeutic targets beyond current amyloid-focused treatments.

Early Memory Impairment in Alzheimer's Mouse Model

• ▪Old APP-KI mice aged 7-11 months showed 67.9% correct trials for new odor associations compared to 84.9% in age-matched wild-type mice
• ▪APP-KI mice show progressive impairment in the formation, but not the retrieval, of associative memory starting at 4 months of age
• ▪Young APP-KI mice aged 3-6 months performed at 78.6% correct trials for new odor associations compared to 90.6% in young wild-type mice at timepoint T5
• ▪Amyloid precursor protein knock-in (APP-KI) mice show age-dependent accumulation of amyloid-β starting widely in cortical regions, including the lateral entorhinal cortex, at 2 months of age
• ▪Young APP-KI mice aged 3-6 months correctly learned new associations in 59.1% of all tested sessions compared to 77.5% in young wild-type mice
• ▪Old APP-KI mice aged 7-11 months correctly learned new associations in 47.3% of all sessions compared to 81.3% in age-matched wild-type mice

Disrupted Neural Activity in Lateral Entorhinal Cortex

• ▪Mean firing rates of putative lateral entorhinal cortex layer 2/3 principal neurons and interneurons were both higher in APP-KI mice than in wild-type mice
• ▪Researchers recorded 479 neurons from 5 young wild-type mice and 846 neurons from 5 young APP-KI mice in lateral entorhinal cortex layer 2/3
• ▪In APP-KI mice, 34% of lateral entorhinal cortex layer 2/3 neurons exhibited cue responses at timepoint T5 compared to 16% in wild-type mice
• ▪Lateral entorhinal cortex layer 2/3 neurons in APP-KI mice showed decreasing spike widths compared to those of wild-type mice
• ▪The percentage of Odor-A responsive cells in lateral entorhinal cortex layer 2/3 was higher in APP-KI mice compared to wild-type mice

Perspective of Alzheimer's disease researchers focusing on amyloid-β pathology

• ▪Entorhinal cortex layer 2 neurons' vulnerability to early-stage Alzheimer's disease makes them a critical target for understanding disease progression
• ▪The lateral entorhinal cortex accumulation of amyloid-β at 2 months in APP-KI mice provides an early disease model for studying Alzheimer's pathophysiology