Objective:

We quantified the level of neurodegeneration and amyloid burden along the radial (superficial, deep) and transverse axes (CA1a, CA1c) in CA1 in a transgenic model of amyloidosis (5xFAD).

Background:

In Alzheimer’s disease (AD), area CA1 bears the brunt of pathology and pyramidal neuron (PN) degeneration within the hippocampus. CA1 PNs are molecularly heterogeneous across anatomical (transverse, radial) axes, yet it is unknown whether this heterogeneity belies differential susceptibility to neurodegeneration in AD. 

Design/Methods:

Fluorescent immunohistochemistry was performed on fixed brain sections prepared from 5xFAD mice and wild type (WT) littermates (3.5 months, 9-16 months old, n = 2-4/group across both sexes). Sections were mounted with DAPI media and imaged via confocal microscopy to visualize NeuN positive cells. Amyloid plaque was visualized with the AB1-42 antibody. Images were analyzed using ImageJ for cell density in superficial and deep layers of CA1a and CA1c. Amyloid plaque burden was quantified in CA1a and CA1c. 

Results:

At 3.5 months, there was no significant difference in cell density across genotypes among PN subpopulations. At 9-16 months, there was a 35% reduction of cell density in the CA1a superficial layer in 5xFAD versus WT mice (p = 0.0195). A similar but smaller trend was observed in the CA1c superficial layer (27% reduction, p = 0.06). The deep layer in CA1a and CA1c did not show significant changes in cell density across genotype. Amyloid pathology burden was found to impact CA1a more than CA1c. 

Conclusions:

Superficial CA1 PNs are selectively vulnerable to neurodegeneration compared to deep CA1 PNs. This is more evident in CA1a than in CA1c, tracking with amyloid plaque burden. This promotes further work to link specific baseline molecular and functional differences between CA1 PN subpopulations to their vulnerability to amyloid, as a means to understand memory deficits and reveal novel susceptibility and resilience mechanisms.