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. 2013 Dec;136(Pt 12):3738-52.
doi: 10.1093/brain/awt273. Epub 2013 Oct 17.

Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles

Carlos Humberto Andrade-Moraes  1 , Ana V Oliveira-Pinto, Emily Castro-Fonseca, Camila G da Silva, Daniel M Guimarães, Diego Szczupak, Danielle R Parente-Bruno, Ludmila R B Carvalho, Lívia Polichiso, Bruna V Gomes, Lays M Oliveira, Roberta D Rodriguez, Renata E P Leite, Renata E L Ferretti-Rebustini, Wilson Jacob-Filho, Carlos A Pasqualucci, Lea T Grinberg, Roberto Lent
Affiliations

Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles

Carlos Humberto Andrade-Moraes et al. Brain. 2013 Dec.

Abstract

Alzheimer's disease is the commonest cause of dementia in the elderly, but its pathological determinants are still debated. Amyloid-β plaques and neurofibrillary tangles have been implicated either directly as disruptors of neural function, or indirectly by precipitating neuronal death and thus causing a reduction in neuronal number. Alternatively, the initial cognitive decline has been attributed to subtle intracellular events caused by amyloid-β oligomers, resulting in dementia after massive synaptic dysfunction followed by neuronal degeneration and death. To investigate whether Alzheimer's disease is associated with changes in the absolute cell numbers of ageing brains, we used the isotropic fractionator, a novel technique designed to determine the absolute cellular composition of brain regions. We investigated whether plaques and tangles are associated with neuronal loss, or whether it is dementia that relates to changes of absolute cell composition, by comparing cell numbers in brains of patients severely demented with those of asymptomatic individuals-both groups histopathologically diagnosed as Alzheimer's-and normal subjects with no pathological signs of the disease. We found a great reduction of neuronal numbers in the hippocampus and cerebral cortex of demented patients with Alzheimer's disease, but not in asymptomatic subjects with Alzheimer's disease. We concluded that neuronal loss is associated with dementia and not the presence of plaques and tangles, which may explain why subjects with histopathological features of Alzheimer's disease can be asymptomatic; and exclude amyloid-β deposits as causes for the reduction of neuronal numbers in the brain. We found an increase of non-neuronal cell numbers in the cerebral cortex and subcortical white matter of demented patients with Alzheimer's disease when compared with asymptomatic subjects with Alzheimer's disease and control subjects, suggesting a reactive glial cell response in the former that may be related to the symptoms they present.

Keywords: ageing; amyloid-β; dementia; isotropic fractionator; neuronal loss.

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Figures

Figure 1
Figure 1
After removing the meninges and blood vessels (A), the left brainstem and cerebellum were separated from the brain (B), and the cerebellar peduncles were cut to isolate the cerebellum (C). The hippocampal formation was removed out from the hemisphere by sectioning along the collateral sulcus until the caudalmost coronal level of the callosal splenium (D). The frontal lobe was then separated from the rest of the brain by a section made along the central sulcus (E), and cut coronally into slices of ∼1 cm thickness (E and F). Finally (F), the cerebral cortex was separated from the remaining regions (basal ganglia, diencephalon, mesencephalon, pons and medulla oblongata).
Figure 2
Figure 2
Histopathological features of some cases, taken from sections through the inferior temporal cortex. Upper row (A, C and E), immunostaining for amyloid-β, and lower row (B, D and F), immunostaining for phospho-Tau (see ‘Materials and methods’ section for details). (A and B) Control (CTRL; 82 years, Clinical Dementia Rating Scale = 0, Braak II; see Table 1), showing no signs of pathology. (C and D) Demented patient with Alzheimer’s disease (AD, 74 years, Clinical Dementia Rating Scale = 3, Braak IV), with an abundant number of neuritic plaques (in brown). (E and F) Asymptomatic subject with Alzheimer’s disease (ASYMAD, 82 years, Clinical Dementia Rating Scale = 0, Braak V), showing an advanced pattern of Alzheimer’s pathology. Neurofibrillary tangles are indicated with arrows, and neuritic plaques indicated with circles in D and F. Scale bars: A, C and E = 1 mm; B, D and F = 100 µm.
Figure 3
Figure 3
Absolute bilateral cell number (A and C) and density (B and D) of cerebellar (A and B) and hippocampal formation (C and D) neuronal, non-neuronal, and total cells in control, asymptomatic Alzheimer’s disease (ASYMAD) and demented Alzheimer’s disease (AD) groups. Each bar represents mean and standard deviation. Significant differences are indicated by *P < 0.05, **P < 0.01.
Figure 4
Figure 4
Absolute bilateral cell number (A, C, E, and G) and density (B, D, F, and H) for neuronal, non-neuronal, and total cells in the grey (A and B) and white (C and D) matter of the frontal lobe (A–D) and of the other lobes as a whole (E–H) from control, asymptomatic Alzheimer’s disease (ASYMAD) and demented Alzheimer’s disease (AD) groups. Each bar represents the mean and standard deviation. Significant differences are indicated by *P < 0.05, **P < 0.01, and ***P < 0.001.
Figure 5
Figure 5
Absolute bilateral cell number (A and C) and density (B and D) for neuronal, non-neuronal, and total cells in the grey (A and B) and white (C and D) matter of the entire cerebral cortex from control, asymptomatic Alzheimer’s disease (ASYMAD) and demented Alzheimer’s disease (AD) groups. Each bar represents the mean and standard deviation. Significant differences are indicated by *P < 0.05, **P < 0.01, and ***P < 0.001.
Figure 6
Figure 6
Absolute bilateral cell number (A) and density (B) for neuronal, non-neuronal, and total cells in the whole brain from control, asymptomatic Alzheimer’s disease (ASYMAD) and demented Alzheimer’s disease (AD) groups. Each bar represents the mean and standard deviation. Significant differences are indicated by *P < 0.05, **P < 0.01, and ***P < 0.001.
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