Dendritic spine remodeling accompanies Alzheimer's disease pathology and genetic susceptibility in cognitively normal aging

Abstract

Subtle alterations in dendritic spine morphology can induce marked effects on connectivity patterns of neuronal circuits and subsequent cognitive behavior. Past studies of rodent and nonhuman primate aging revealed reductions in spine density with concomitant alterations in spine morphology among pyramidal neurons in the prefrontal cortex. In this report, we visualized and digitally reconstructed the three-dimensional morphology of dendritic spines from the dorsolateral prefrontal cortex in cognitively normal individuals aged 40-94 years. Linear models defined relationships between spines and age, Mini-Mental State Examination, apolipoprotein E (APOE) ε4 allele status, and Alzheimer's disease (AD) pathology. Similar to findings in other mammals, spine density correlated negatively with human aging. Reduced spine head diameter associated with higher Mini-Mental State Examination scores. Individuals harboring an APOE ε4 allele displayed greater numbers of dendritic filopodia and structural alterations in thin spines. The presence of AD pathology correlated with increased spine length, reduced thin spine head diameter, and increased filopodia density. Our study reveals how spine morphology in the prefrontal cortex changes in human aging and highlights key structural alterations in selective spine populations that may promote cognitively normal function despite harboring the APOE ε4 allele or AD pathology.

Keywords: APOE; Aging; Alzheimer's disease; Dementia; Dendritic spine; Prefrontal cortex; Resiliency.

Figure 1.

Highly optimized three-dimensional modeling of dendritic spines in humans. (A, C, E, G) Representative brightfield images of Golgi-impregnated dendrites from 40, 64, 82, and 94 year old individuals. Scale bars represent 3 μm. (B, D, F, H) Three-dimensional digital reconstructions of the same dendrites generated in Neurolucida360. Thin spines are blue, stubby spines are orange, mushroom spines are green, and filopodia are yellow.

Figure 2.

Dendritic spine density is reduced in human aging. For each case, the number of spines per 10 μm was determined for 10–20 dendrites and averaged to generate a case mean. Linear regression analyses examined the relationship between age at death with individual spine phenotypes. (A) The density of spines per 10 μm of dendrite was plotted against the age of each case. Age at death is presented in years, and each dot represents one case. There is negative correlation between age and spine density. (B) Distribution of spine density measured per 10 μm of dendrite. Each dot represents the average spine density per 10 μm for each dendrite that was imaged. Individual cases represented by age in years. (C) Linear regression analysis of spine density measured per 10 μm of dendrite across all cases with postmortem interval (PMI). Each dot represents the average spine density per 10 μm for each individual case. The density of spines per 10 μm of dendrite was plotted against the PMI for each individual. PMI represented in hours. (D) Linear regression analysis of spine classification densities measured per 10 μm of dendrite in all cases with age. Each dot represents the average spine class density per 10 μm for each individual case. The density of spine class per 10 μm of dendrite was plotted against the age of each individual. Age represented in years. (E) Linear regression analysis examined the relationship between mean spine length and age of each case. To illustrate an example of what was measured, the inset depicts a brightfield image of a thin spine with length traced in blue. (F) Linear regression analysis examined the relationship between mean spine head diameter and age of each case. The inset depicts a brightfield image of a thin spine with head diameter traced in blue.

Figure 3.

Mini-Mental State Examination (MMSE) score associates with dendritic spine head diameter. (A) The relationship between spine density per 10 μm and MMSE score was plotted. (B) Linear regression analysis of spine classification densities measured per 10 μm of dendrite in all cases with MMSE score. Each dot represents the average spine class density per 10 μm for each individual case. (C) The relationship between spine length and MMSE score was plotted for each case. (D) The relationship between spine head diameter and MMSE score was plotted for each case.

Figure 4.

Increased filopodia density and reduced thin spine head diameter associate with the APOE ε4 allele. (A) Mean number of spines per 10 μm was calculated for each case and plotted based on ε4 status. (B) Mean number of spine classification densities per 10 μm was calculated for each case and plotted based on ε4 status. The inset depicts a brightfield image of a mushroom spine. (C) Mean number of filopodia per 100 μm was calculated for each case and plotted based on ε4 status. The inset depicts a brightfield image of a filopodia. (D) Mean spine length was determined for each case and plotted based on ε4 status. (E) Mean spine head diameter was determined for each case and plotted based on ε4 status. (F) Mean head diameter of thin spines was determined for each case and plotted based on ε4 status. To illustrate an example of what was measured, the inset depicts brightfield image of thin spine with head diameter traced in blue. Lines represent the mean ± standard error of the mean. **P = 0.008 and *** P = 0.001.

Figure 5.

Selective spine phenotypes associate with CERAD score or Braak Stage. (A) The relationship between spine density per 10 μm and CERAD score was plotted. (B) The relationship between spine density per 10 μm and Braak Stage was plotted. (C) Linear regression analysis of spine classification densities measured per 10 μm of dendrite in all cases with CERAD score. Each dot represents the average spine class density per 10 μm for each individual case. (D) Linear regression analysis of spine classification densities measured per 10 μm of dendrite in all cases with Braak Stage. Filopodia density per 100 μm was plotted against (E) CERAD score or (F) Braak Stage for each case. The relationship between spine length and (G) CERAD score or (H) Braak Stage was plotted for each case. The relationship between spine head diameter and (I) CERAD score or (J) Braak Stage was plotted for each case. Linear regression analysis detected a negative relationship between (K) CERAD score or (L) Braak Stage and thin spine head diameter.