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06-09-2011 | General practice | Article

Glial cells may play central role in AD neurodegeneration


Free abstract

MedWire News: In Alzheimer's disease (AD) amyloid plaque load appears to reach a plateau early after symptom onset whereas associated glial cells increase linearly through the entire clinical course of the disease, results of a post-mortem brain bank study show.

The findings "argue against a straightforward relationship between glial cells and plaques" and also "suggest that reactive glia might contribute to the ongoing neurodegeneration," according to Bradley Hyman (Massachusetts General Hospital, Charlestown, USA) and colleagues.

Amyloid plaques are a hallmark of AD, but recent studies have shown that, while both neuronal and synaptic loss correlate with the severity of cognitive impairment, amyloid plaque burden does not.

Thus attention has turned to factors and cells that cluster around amyloid plaque such as glial cells - which are the non-neuronal supporting cells of the central nervous system and brain. In particular, aberrantly activated glial cells, including microglia (which are phagocytic cells) and astrocytes, have been linked to AD progression.

In a previous study, the researchers found a positive linear correlation between astrocytosis in the temporal neocortex and the duration of the disease from the onset of cognitive symptoms, despite the plaque burden remaining stable throughout the course of the disease.

They aimed to extend this work in the present study by reviewing tissue specimens from the temporal association isocortex (Brodmann area 38) of 91 patients with AD obtained from the Massachusetts Alzheimer Disease Research Center Brain Bank.

They also analysed samples from 21 elderly controls with no dementia, enabling them to to trace the natural history of brain amyloidosis as a continuum between normal aging and various stages of AD.

Amyloid burden, defined as the percentage of cortical surface immunoreactive for the anti-Aβ antibody 10D5, reached a plateau early after symptom onset and remained relatively stable thereafter.

Despite being traditionally regarded as plaque-associated pathologic features, the progression of astrocytic and microglial responses differed from that of amyloid plaques both qualitatively and quantitatively. Both reactive glial cell types increased linearly through the entire clinical course of the disease, even when the amyloid burden was no longer increasing.

Neither astrocytosis nor microgliosis correlated with the amyloid burden or the total number of plaques. Unlike the measures of amyloid deposition, both astrocytosis and microgliosis correlated positively with the neurofibrillary tangles (NFT) burden.

Hyman et al say their work could have implications for the development of imaging biomarkers and disease modifying drugs.

"If glial responses become partially independent from amyloid plaques and their contribution to neurodegeneration is relevant, then removal of amyloid plaques with anti-Aβ-directed therapies, such as passive or active immunization, might not be sufficient to block this neurotoxicity.

"Glia-mediated inflammation has already been considered as a therapeutic target."

The findings are published in the American Journal of Pathology.

By Andrew Czyzewski

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