Journal
BRAIN
Volume 136, Issue -, Pages 3738-3752Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awt273
Keywords
ageing; amyloid-beta; dementia; neuronal loss; isotropic fractionator
Categories
Funding
- Brazilian Council for Science and Technology Development (CNPq)
- Rio de Janeiro Foundation for the Support of Science (FAPERJ)
- Brazilian Ministry of Science, Technology and Innovation (Program of National Institutes of Science and Technology, MCTI-INCTs)
- CAPES
- NIH [R01AG040311-01]
- Sao Paulo Foundation for the Support of Science (FAPESP)
- FAPESP
- LIM-22 FMUSP
- Hospital Israelita Albert Einstein
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Alzheimer's disease is the commonest cause of dementia in the elderly, but its pathological determinants are still debated. Amyloid-beta 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-beta 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-beta 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.
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