Abstract

Background: Significant reductions in dendritic spine density have been observed for patients with cognitive impairment and Alzheimer's disease (AD) pathology, while spine density between cognitively normal control patients and cognitively normal patients with AD pathology is similar. These data provide evidence to support the hypothesis that resilience to dendritic spine loss protects against cognitive decline due to AD. Methods: To identify possible mechanisms underlying the association between cognitive resilience and spine loss, spine morphometry statistics were gathered in cognitively resilient and susceptible mice from the AD-BXD mouse panel. The AD-BXD panel incorporates five high-risk familial AD mutations (APP K670N/M671L [Swedish] + I716V [Florida] + V717I [London] and PS1 M146L+ L286V) on different strains from the BXD reference panel (BXD; C57BL/6J x DBA/2J). Cognition was assessed using the contextual fear conditioning (CFC) behavioral task in 14-month-old, female AD-BXD mice (B6xB6, B6xD2, B6xBXD99, and B6xBXD124 strains) and Ntg-BXD littermate controls, with contextual fear memory (CFM; ie, % freezing) being assessed on Day 2 of the paradigm. Based on a mean CFM cutoff score of 40.3% freezing, mice were grouped into the following categories: Ntg-BXD cognitively normal, AD-BXD resilient, and AD-BXD susceptible. Following CFC, brains were harvested, and dentate granule cells (DGC) were filled with biocytin and then stained with streptavidin-488. Images were acquired with a Leica Stellaris 5 confocal microscope (63x, 1.4 NA). Deconvoluted images were imported into Neurolucida 360 (v2023.1.1, MBF Bioscience, Williston, Vermont) for 3D reconstruction of dendritic spines and analyzed in Neurolucida Explorer to gather dendritic spine density (#/µm) and morphological classification (ie, mushroom, thin, and stubby) data. All data were statistically analyzed and graphed using R Studio or GraphPad Prism 10.0. Results: Total spine density in DGCs was found to be the lowest in cognitively susceptible AD-BXD mice, but not significantly associated with cognitive performance (R2 = 0.1004, p = 0.0724). A significant positive association was observed between thin spine density and cognitive performance (R2 = 0.2073, p = 0.0078), but not between stubby or mushroom spine density and cognition, respectively (R2 = 0.0872, p = 0.0953; R2 = 0.0009, p = 0.8662). Conclusions: While a significant association was not observed between total, stubby, and mushroom spine density and cognition, respectively, a significant positive association was found between thin spine density and cognitive performance. Thin spines are characterized by a smaller head and a longer neck; they are thought to be more dynamic and more able to readily change their structure. Thin spines are often involved in synaptic plasticity and are associated with learning and memory. These data suggest that thin spine preservation in mice with AD protects against cognitive decline, and will allow future analyses to determine the genetic contributions to spine morphometry and its relationship to cognitive resilience in AD.