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[P3–177]: STRUCTURAL REMODELING OF DENDRITIC SPINES PROVIDES COGNITIVE RESILIENCE AGAINST ALZHEIMER's DISEASE PATHOLOGY
Author(s) -
Boros Benjamin D.,
Gentry Erik G.,
Birchall Elizabeth L.,
Gearing Marla,
Herskowitz Jeremy H.
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.1389
Subject(s) - dendritic spine , neuroscience , dendrite (mathematics) , dementia , prefrontal cortex , autopsy , apical dendrite , pathology , neuropathology , cortex (anatomy) , psychology , medicine , cognition , biology , disease , cerebral cortex , hippocampal formation , geometry , mathematics
Background:Approximately 30-50% of individuals who come to autopsy without dementia have high levels of AD pathology. These cases are proposed to represent individuals who are resilient to dementia, but how cognitively normal older individuals with AD pathophysiology withstand the development of dementia has remained one of the most pivotal, unanswered questions in the field. Here we used innovative, highly optimized three-dimensional modeling of dendritic spines to analyze synapse populations from controls, cognitively normal individuals with high AD pathology, and AD dementia cases. Our analysis shows that dendritic spines undergo unique structural remodeling exclusively in patients with high AD pathology but no cognitive impairment. Our discovery is the first neurobiological evidence for cognitive resilience in humans with AD pathology. Methods: Samples included postmortem human prefrontal cortex tissue from age-matched pathology-free controls, controls with high levels of AD pathology, and late-onset AD cases. Methods included GolgiCox technique, brightfield imaging, three-dimensional digital reconstruction and morphological analysis of dendritic spines. Results: We compared the density of dendritic spines within layers II and III pyramidal neuron dendrites in Brodmann Area 46 (BA46) dorsolateral prefrontal cortex (DLPFC), a key area of working memory, using the Golgi-Cox technique in control, resilient to AD (RAD), and AD cases. We developed a method to digitally trace impregnated dendrites from brightfield microscopy images, enabling accurate three-dimensional reconstruction of dendritic structure. Spine density, measured per dendrite length or dendrite surface area, was similar among control and RAD cases but reduced significantly in AD. Analysis of spine morphology revealed that spine extent was increased significantly and exclusively in RAD cases compared to controls and AD, whereas spine head diameter was similar among disease states. Comparison of thin, stubby, and mushroom spine populations revealed that thin spines were selectively lost in AD cases. Conclusions:Our findings support the hypothesis that spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathophysiology from developing dementia and highlight structural plasticity as a substrate for therapeutic intervention to delay dementia onset during the preclinical phase of AD.