Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele

Abstract

A relationship between the apolipoprotein E (apoE) genotype and the risk to develop Alzheimer's disease has been established recently. Apolipoprotein synthesis is implicated in developmental processes and in neuronal repair of the adult nervous system. In the present study, we investigated the influence of the apolipoprotein polymorphism on the severity of neuronal degeneration and the extent of plastic dendritic remodeling in Alzheimer's disease. Changes in length and arborization of dendrites of Golgi-impregnated neurons in the basal nucleus of Meynert, locus coeruleus, raphe magnus nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra were analyzed after three-dimensional reconstruction. Patients with either one or two apoE epsilon 4 alleles not only showed a more severe degeneration in all areas investigated than in patients lacking the apoE 4 allele but also revealed significantly less plastic dendritic changes. ApoE epsilon 4 allele copy number, furthermore, had a significant effect on the pattern of dendritic arborization. Moreover, the relationship between the intensity of dendritic growth and both the extent of neuronal degeneration and the stage of the disease seen in patients lacking the apoE epsilon 4 allele was very weak in the presence of one epsilon 4 allele and completely lost in patients homozygous for the epsilon 4 allele. The results provide direct evidence that neuronal reorganization is affected severely in patients with Alzheimer's disease carrying the apoE epsilon 4 allele. This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease.

Fig. 1.

Cluster of Golgi-impregnated reticular neurons in the basal nucleus of Meynert in a patient with AD.Inset, Two-dimensional projection of the three-dimensional image reconstructed from serial sections. Scale bar, 50 μm.

Fig. 2.

Changes in the total number of dendritic segments and in the frequency distribution of segments obtained for different orders on Golgi-impregnated reticular neurons in different subgroups of patients with AD, as compared with controls (centrifugal system of ordering, i.e., primary segments correspond to order 1; most distal branches correspond to highest segment order). Open columns, Control values; open pluscross-hatched columns, AD patients. Data are mean values. For each case, 300 neurons were analyzed. For group size, see Table 1; for summary of statistical analysis, compare Table 3.

Fig. 2.

Changes in the total number of dendritic segments and in the frequency distribution of segments obtained for different orders on Golgi-impregnated reticular neurons in different subgroups of patients with AD, as compared with controls (centrifugal system of ordering, i.e., primary segments correspond to order 1; most distal branches correspond to highest segment order). Open columns, Control values; open pluscross-hatched columns, AD patients. Data are mean values. For each case, 300 neurons were analyzed. For group size, see Table 1; for summary of statistical analysis, compare Table 3.

Fig. 3.

Relationship between the loss of neurons and the extent of dendritic growth in subcortical brain areas separately analyzed for different subgroups of patients with AD. Analyses of linear regression were performed, and correlation coefficients according to Bravais–Pearson were calculated. For group size, see Table 1.

Fig. 4.

Differences in the reparative capacity of patients with AD grouped according to their apoE genotypes. Student’st tests were used to compare individual group means ± SEM. For group size, see Table 1.

Fig. 5.

Relationship between the dendritic growth and reparative capacity of reticular neurons in subcortical brain areas and the clinical stage of AD, assessed according to FAST. Different subgroups of patients classified according to their apoE genotypes were compared by ANOVA (effect, subgroup × linear trend of disease progression). df, apoE 3/3 versus apoE 3/4, 1, 51; apoE 3/3 versus apoE 4/4, 1, 43; apoE 3/4 versus apoE 4/4, 1, 28; for both dendritic growth and reparative capacity, all p < 0.01. For group size, see Table 1; for analysis of linear regression, compare Table4.

Fig. 6.

Ratio between ChAT activity in the cerebral cortex and number of cholinergic neurons in the basal nucleus of Meynert in patients with AD carrying different apoE genotypes. Values of both ChAT activity and neuronal number (determined on every 20th section processed for anti-ChAT immunocytochemistry) are expressed as percentages of control values. Student’s t tests were used to compare mean values of individual groups; allp < 0.001. For group size, see Table 1.