Marutle_2013_J.Neuroinflammation_10_90

BACKGROUND: The pathological features in Alzheimer's disease (AD) brain include the accumulation and deposition of beta-amyloid (Abeta), activation of astrocytes and microglia and disruption of cholinergic neurotransmission. Since the topographical characteristics of these different pathological processes in AD brain and how these relate to each other is not clear, this motivated further exploration using binding studies in postmortem brain with molecular imaging tracers. This information could aid the development of specific biomarkers to accurately chart disease progression.
RESULTS: In vitro binding assays demonstrated increased [(3)H]-PIB (fibrillar Abeta) and [(3)H]-PK11195 (activated microglia) binding in the frontal cortex (FC) and hippocampus (HIP), as well as increased binding of [(3)H]-L-deprenyl (activated astrocytes) in the HIP, but a decreased [(3)H]-nicotine (alpha4beta2 nicotinic acetylcholine receptor (nAChR)) binding in the FC of AD cases compared to age-matched controls. Quantitative autoradiography binding studies were also performed to investigate the regional laminar distributions of [(3)H]-L-deprenyl, [(3)H]-PIB as well as [(1)(2)(5)I]-alpha-bungarotoxin (alpha7 nAChRs) and [(3)H]-nicotine in hemisphere brain of a typical AD case. A clear lamination pattern was observed with high [(3)H]-PIB binding in all layers and [(3)H]-deprenyl in superficial layers of the FC. In contrast, [(3)H]-PIB showed low binding to fibrillar Abeta, but [(3)H]-deprenyl high binding to activated astrocytes throughout the HIP. The [(3)H]-PIB binding was also low and the [(3)H]-deprenyl binding high in all layers of the medial temporal gyrus and insular cortex in comparison to the frontal cortex. Low [(3)H]-nicotine binding was observed in all layers of the frontal cortex in comparison to layers in the medial temporal gyrus, insular cortex and hippocampus. Immunohistochemical detection in the AD case revealed abundant glial fibrillary acidic protein positive (GFAP+) reactive astrocytes and alpha7 nAChR expressing GFAP+ astrocytes both in the vicinity and surrounding Abeta neuritic plaques in the FC and HIP. Although fewer Abeta plaques were observed in the HIP, some hippocampal GFAP+ astrocytes contained Abeta-positive (6 F/3D) granules within their somata.
CONCLUSIONS: Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar Abeta, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.