A Phenotypic Change But Not Proliferation Underlies Glial Responses in Alzheimer Disease

• Published in: The American journal of pathology Vol. 182; no. 6; pp. 2332 - 2344
• Main Authors: Serrano-Pozo, Alberto, Gómez-Isla, Teresa, Growdon, John H., Frosch, Matthew P., Hyman, Bradley T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2013; American Society for Investigative Pathology
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Astrocytes - metabolism; Astrocytes - pathology; Atrophy - pathology; Case-Control Studies; Cell Count; Cell Proliferation; Female; Glial Fibrillary Acidic Protein - metabolism; Histocompatibility Antigens Class II - metabolism; Humans; Male; Microglia - metabolism; Microglia - pathology; Microscopy, Confocal; Pathology; Phenotype; Regular; Temporal Lobe - metabolism; Temporal Lobe - pathology
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2013.02.031

Classical immunohistochemical studies in the Alzheimer disease (AD) brain reveal prominent glial reactions, but whether this pathological feature is due primarily to cell proliferation or to a phenotypic change of existing resting cells remains controversial. We performed double-fluorescence immunohistochemical studies of astrocytes and microglia, followed by unbiased stereology-based quantitation in temporal cortex of 40 AD patients and 32 age-matched nondemented subjects. Glial fibrillary acidic protein (GFAP) and major histocompatibility complex II (MHC2) were used as markers of astrocytic and microglial activation, respectively. Aldehyde dehydrogenase 1 L1 and glutamine synthetase were used as constitutive astrocytic markers, and ionized calcium-binding adaptor molecule 1 (IBA1) as a constitutive microglial marker. As expected, AD patients had higher numbers of GFAP+ astrocytes and MHC2+ microglia than the nondemented subjects. However, both groups had similar numbers of total astrocytes and microglia and, in the AD group, these total numbers remained essentially constant over the clinical course of the disease. The GFAP immunoreactivity of astrocytes, but not the MHC2 immunoreactivity of microglia, increased in parallel with the duration of the clinical illness in the AD group. Cortical atrophy contributed to the perception of increased glia density. We conclude that a phenotypic change of existing glial cells, rather than a marked proliferation of glial precursors, accounts for the majority of the glial responses observed in the AD brain.