Resistance to Alzheimer's pathology is associated with nuclear hypertrophy in neurons

Abstract

This study focuses on the morphometric changes of neurons in asymptomatic Alzheimer's disease (AD), a state characterized by the presence of AD lesions in subjects without cognitive impairment. In autopsy brains, we used stereological methods to compare the cell body and nuclear volumes of anterior cingulate gyrus (ACG) and CA1 hippocampal neurons in asymptomatic AD subjects (n=9), subjects with AD dementia (AD, n=8), mild cognitive impairment (MCI, n=9), and age-matched controls (controls, n=9). In ACG, we observed a significant decrease in the neuronal volume of MCI and AD compared to controls; by contrast, no atrophy was present in asymptomatic AD. Moreover, we found a significant increase in nuclear volume in asymptomatic AD compared to controls (P<0.001), MCI (P<0.01) and AD (P<0.001) brains. Similar results were found in the CA1 region of the hippocampus. This nuclear hypertrophy may represent an early neuronal reaction to Abeta or Tau, or a compensatory mechanism which forestalls the progression of AD and allows the brain to resist the development of dementia.

A novel hypothesis for Alzheimer disease based on neuronal tetraploidy induced by p75NTR

“…65,69 Analysis of brains of individuals with asymptomatic AD (i.e., showing histopathological signs of AD without evident cognitive deficits) has demonstrated hypertrophy in hippocampal neurons, not only of nuclei and nucleoli but also of cell bodies. [70][71][72][73] This observation is consistent with hypertrophy being an early feature of AD, and it suggests that under certain circumstances tetraploid neurons can be maintained for extremely long periods without soma shrinkage, thus maintaining normal function despite the presence of NFT and deposits of Aβ.…”

“…Firstly, genome duplication could result in changes of gene expression that would functionally compromise affected neurons. This might be evidenced by the presence of large nucleoli in the hypertrophic neurons in asymptomatic AD, [70][71][72][73] suggesting enhanced mRNA expression in the affected neurons. Genome multiplication in mammals has been associated with alterations in a wide range of cellular processes, including enhanced protein turnover and transcriptional rate, shift from aerobic to anaerobic metabolism, and stress response.…”

Amyloid precursor protein increases cortical neuron size in transgenic mice

“…Sampling sites were selected with a grid size of 300 μm × 300 μm, and the counting frame was 45 μm × 35 μm. The cortical neuron cell volumes were measured with the Nucleator probe as described previously (Riudavets et al, 2007). Minimum of 100 neurons were measured per section.…”

“…For example, most of these animals do not develop tau lesions and many do not show loss of neurons (Irizarry et al, 1997a, b ). In this study, to further explore the parallels between the pathology of these animal models and that of human AD, we set out to examine whether cortical neurons in mouse models of AD undergo atrophy similar to that described in various stages of AD (Riudavets et al, 2007). To this end, we compared the cortical neuron volumes of tg mouse models overexpressing the familial AD Swedish mutation (APPswe), the PS1 mutation (PS1dE9), and their combination (APPswe/PS1dE9) to those of their non-transgenic (ntg) littermates.…”

Metabolic changes in the anterior and posterior cingulate cortices of the normal aging brain: proton magnetic resonance spectroscopy study at 3 T

“…Recently, no brain atrophy and, in fact, neuronal hypertrophy were found in asymptomatic Alzheimer's disease (Iacono et al 2008;O'Brien et al 2009;Riudavets et al 2007). In the Baltimore Longitudinal Study of Aging autopsy series, asymptomatic Alzheimer's disease represented approximately 50 % of individuals with preserved cognition beyond 75 years of age, who tended to overlap with normal aging clinically.…”