Journal
JOURNAL OF NEUROINFLAMMATION
Volume 10, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1742-2094-10-90
Keywords
Alzheimer's disease; Postmortem brain; Laminar pathology; Astrogliosis; Microgliosis; Fibrillar amyloid; Nicotinic acetylcholine receptors; PIB; Quantitative autoradiography
Categories
Funding
- Swedish Research Council [05817]
- Swedish Brain Power
- Stockholm County Council-Karolinska Institutet (ALF)
- Karolinska Institutet
- Swedish Brain Foundation
- EC FP project DIMI
- LSHB [CT2005 512146]
- European Union [Health-F2-2011-278850]
- Alzheimer Foundation in Sweden
- Magnus Bergvalls Foundation
- Dementia Association
- Foundation for Old Servants
- Gun and Bertil Stohnes Foundation
- Ragnhild och Einar Lundstroms Memorial Foundation
- Karolinska Institutet's Foundation for Aging Research
- Lars Hierta Memorial Foundation
- Loo and Hans Ostermans Foundation
- Olle Engkvist Byggmastare Foundation
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Background: The pathological features in Alzheimer's disease (AD) brain include the accumulation and deposition of beta-amyloid (A beta), 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 [H-3]-PIB (fibrillar A beta) and [H-3]-PK11195 (activated microglia) binding in the frontal cortex (FC) and hippocampus (HIP), as well as increased binding of [H-3]-L-deprenyl (activated astrocytes) in the HIP, but a decreased [3H]-nicotine (alpha 4 beta 2 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 [H-3]-L-deprenyl, [H-3]-PIB as well as [I-125]-alpha-bungarotoxin (alpha 7 nAChRs) and [H-3]-nicotine in hemisphere brain of a typical AD case. A clear lamination pattern was observed with high [H-3]-PIB binding in all layers and [H-3]-deprenyl in superficial layers of the FC. In contrast, [H-3]-PIB showed low binding to fibrillar A beta, but [H-3]-deprenyl high binding to activated astrocytes throughout the HIP. The [H-3]-PIB binding was also low and the [H-3]-deprenyl binding high in all layers of the medial temporal gyrus and insular cortex in comparison to the frontal cortex. Low [H-3]-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 alpha 7 nAChR expressing GFAP(+) astrocytes both in the vicinity and surrounding A beta neuritic plaques in the FC and HIP. Although fewer A beta plaques were observed in the HIP, some hippocampal GFAP(+) astrocytes contained A beta-positive (6 F/3D) granules within their somata. Conclusions: Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar A beta, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.
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