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³H-deprenyl and ³H-PIB autoradiography show different laminar distributions of astroglia and fibrillar β-amyloid in Alzheimer brain.

Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I, Voytenko L, Nordberg A - J Neuroinflammation (2013)

Bottom Line: In vitro binding assays demonstrated increased [³H]-PIB (fibrillar Aβ) and [³H]-PK11195 (activated microglia) binding in the frontal cortex (FC) and hippocampus (HIP), as well as increased binding of [³H]-L-deprenyl (activated astrocytes) in the HIP, but a decreased [³H]-nicotine (α4β2 nicotinic acetylcholine receptor (nAChR)) binding in the FC of AD cases compared to age-matched controls.Although fewer Aβ plaques were observed in the HIP, some hippocampal GFAP+ astrocytes contained Aβ-positive (6 F/3D) granules within their somata.Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar Aβ, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum Floor-5, Stockholm S-14186, Sweden.

ABSTRACT

Background: The pathological features in Alzheimer's disease (AD) brain include the accumulation and deposition of β-amyloid (Aβ), 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 [³H]-PIB (fibrillar Aβ) and [³H]-PK11195 (activated microglia) binding in the frontal cortex (FC) and hippocampus (HIP), as well as increased binding of [³H]-L-deprenyl (activated astrocytes) in the HIP, but a decreased [³H]-nicotine (α4β2 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 [³H]-L-deprenyl, [³H]-PIB as well as [¹²⁵I]-α-bungarotoxin (α7 nAChRs) and [³H]-nicotine in hemisphere brain of a typical AD case. A clear lamination pattern was observed with high [³H]-PIB binding in all layers and [³H]-deprenyl in superficial layers of the FC. In contrast, [³H]-PIB showed low binding to fibrillar Aβ, but [³H]-deprenyl high binding to activated astrocytes throughout the HIP. The [³H]-PIB binding was also low and the [³H]-deprenyl binding high in all layers of the medial temporal gyrus and insular cortex in comparison to the frontal cortex. Low [³H]-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 α7 nAChR expressing GFAP+ astrocytes both in the vicinity and surrounding Aβ neuritic plaques in the FC and HIP. Although fewer Aβ plaques were observed in the HIP, some hippocampal GFAP+ astrocytes contained Aβ-positive (6 F/3D) granules within their somata.

Conclusions: Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar Aβ, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.

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Related in: MedlinePlus

The topographical distribution of reactive astrocytes within the superior frontal gyrus and hippocampus in an Alzheimer's disease case. (A) Histological reconstruction of frontal gyrus gray matter made by the superimposition of identical areas of adjacent sections displaying reactive astrocytes with heterogenous morphologies in the different layers. 6F/3D β-amyloid (Aβ) plaques are in red color, reactive astrocytes positive for glial fibrillary acidic protein (GFAP+) are brown. Representative areas (B-D) are in the right column. (B) A uniform distribution of GFAP+ astrocytes (arrows) with small somata and densely stained neuropil in the superficial layers. (C) In the deeper layers, densely stained GFAP+ astrocytes and neuropil are concentrated around Aβ-neuritic plaques (arrows). (D) In the cortical lamina-VI bordering the white matter, GFAP+ astrocytes (arrows) were distributed more evenly as very few Aβ-neuritic plaques were observed in this region. (E) Histological reconstruction of the hippocampal CA1 and the dentate gyrus showing differences in the localization and intensity of immunoreactivity of GFAP+ astrocytes. GFAP+ astrocytes are brown, the α7nAChRs are gray. Representative areas are displayed in the corresponding inserts (F-I). (F) In the CA1 alveus and stratum oriens, intensely stained small somata of GFAP+/α7nAChRs astrocytes and networks were observed. (G) Throughout the stratum pyramidale, large somata of GFAP+ astrocytes without α7nAChRs (arrows) were found dispersed throughout GFAP+ network. (H) Differences in the intensity of immunoreactivity and the number of GFAP+ astrocytes were detected in the stratum lacunosum-moleculare (upper layer, strong staining) and the molecular layer of the dentate gyrus (bottom layer, weak staining). (I) In the granular layer, weakly stained GFAP+ astrocytes and network (top layer) were accompanied by very strong stained α7nAChR/GFAP+ astrocytes (bottom layer, gray). Videocapture was performed with ×10 (A, E) and ×20 (B-D, F-I) objective lenses magnification.
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Figure 7: The topographical distribution of reactive astrocytes within the superior frontal gyrus and hippocampus in an Alzheimer's disease case. (A) Histological reconstruction of frontal gyrus gray matter made by the superimposition of identical areas of adjacent sections displaying reactive astrocytes with heterogenous morphologies in the different layers. 6F/3D β-amyloid (Aβ) plaques are in red color, reactive astrocytes positive for glial fibrillary acidic protein (GFAP+) are brown. Representative areas (B-D) are in the right column. (B) A uniform distribution of GFAP+ astrocytes (arrows) with small somata and densely stained neuropil in the superficial layers. (C) In the deeper layers, densely stained GFAP+ astrocytes and neuropil are concentrated around Aβ-neuritic plaques (arrows). (D) In the cortical lamina-VI bordering the white matter, GFAP+ astrocytes (arrows) were distributed more evenly as very few Aβ-neuritic plaques were observed in this region. (E) Histological reconstruction of the hippocampal CA1 and the dentate gyrus showing differences in the localization and intensity of immunoreactivity of GFAP+ astrocytes. GFAP+ astrocytes are brown, the α7nAChRs are gray. Representative areas are displayed in the corresponding inserts (F-I). (F) In the CA1 alveus and stratum oriens, intensely stained small somata of GFAP+/α7nAChRs astrocytes and networks were observed. (G) Throughout the stratum pyramidale, large somata of GFAP+ astrocytes without α7nAChRs (arrows) were found dispersed throughout GFAP+ network. (H) Differences in the intensity of immunoreactivity and the number of GFAP+ astrocytes were detected in the stratum lacunosum-moleculare (upper layer, strong staining) and the molecular layer of the dentate gyrus (bottom layer, weak staining). (I) In the granular layer, weakly stained GFAP+ astrocytes and network (top layer) were accompanied by very strong stained α7nAChR/GFAP+ astrocytes (bottom layer, gray). Videocapture was performed with ×10 (A, E) and ×20 (B-D, F-I) objective lenses magnification.

Mentions: To relate the laminar [3H]-l-deprenyl autoradiography binding, the distribution of reactive astrocytes within different layers of the frontal cortex and hippocampal subregions in the single AD case was examined by immunohistochemistry with GFAP as a marker for astrocytosis. Differences in the localization and intensity of GFAP immunoreactive cells were found both within each region as well as between the regions (Figure 7). The distribution in the frontal cortex revealed a layer-specific localization of GFAP+ cells exhibiting heterogeneous morphologies (Figure 7A). A uniform distribution of reactive astrocytes with small somata and dense staining of GFAP+ neuropil was detected in the superficial (Figure 7B). In the deeper layers, GFAP+ astrocytic somata and densely stained neuropil were concentrated around Aβ plaques (Figure 7C). GFAP+ astrocytes were distributed more evenly in the cortical layer bordering the white matter (lamina VI), and very few Aβ plaques were observed in this region (Figure 7D).


³H-deprenyl and ³H-PIB autoradiography show different laminar distributions of astroglia and fibrillar β-amyloid in Alzheimer brain.

Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I, Voytenko L, Nordberg A - J Neuroinflammation (2013)

The topographical distribution of reactive astrocytes within the superior frontal gyrus and hippocampus in an Alzheimer's disease case. (A) Histological reconstruction of frontal gyrus gray matter made by the superimposition of identical areas of adjacent sections displaying reactive astrocytes with heterogenous morphologies in the different layers. 6F/3D β-amyloid (Aβ) plaques are in red color, reactive astrocytes positive for glial fibrillary acidic protein (GFAP+) are brown. Representative areas (B-D) are in the right column. (B) A uniform distribution of GFAP+ astrocytes (arrows) with small somata and densely stained neuropil in the superficial layers. (C) In the deeper layers, densely stained GFAP+ astrocytes and neuropil are concentrated around Aβ-neuritic plaques (arrows). (D) In the cortical lamina-VI bordering the white matter, GFAP+ astrocytes (arrows) were distributed more evenly as very few Aβ-neuritic plaques were observed in this region. (E) Histological reconstruction of the hippocampal CA1 and the dentate gyrus showing differences in the localization and intensity of immunoreactivity of GFAP+ astrocytes. GFAP+ astrocytes are brown, the α7nAChRs are gray. Representative areas are displayed in the corresponding inserts (F-I). (F) In the CA1 alveus and stratum oriens, intensely stained small somata of GFAP+/α7nAChRs astrocytes and networks were observed. (G) Throughout the stratum pyramidale, large somata of GFAP+ astrocytes without α7nAChRs (arrows) were found dispersed throughout GFAP+ network. (H) Differences in the intensity of immunoreactivity and the number of GFAP+ astrocytes were detected in the stratum lacunosum-moleculare (upper layer, strong staining) and the molecular layer of the dentate gyrus (bottom layer, weak staining). (I) In the granular layer, weakly stained GFAP+ astrocytes and network (top layer) were accompanied by very strong stained α7nAChR/GFAP+ astrocytes (bottom layer, gray). Videocapture was performed with ×10 (A, E) and ×20 (B-D, F-I) objective lenses magnification.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 7: The topographical distribution of reactive astrocytes within the superior frontal gyrus and hippocampus in an Alzheimer's disease case. (A) Histological reconstruction of frontal gyrus gray matter made by the superimposition of identical areas of adjacent sections displaying reactive astrocytes with heterogenous morphologies in the different layers. 6F/3D β-amyloid (Aβ) plaques are in red color, reactive astrocytes positive for glial fibrillary acidic protein (GFAP+) are brown. Representative areas (B-D) are in the right column. (B) A uniform distribution of GFAP+ astrocytes (arrows) with small somata and densely stained neuropil in the superficial layers. (C) In the deeper layers, densely stained GFAP+ astrocytes and neuropil are concentrated around Aβ-neuritic plaques (arrows). (D) In the cortical lamina-VI bordering the white matter, GFAP+ astrocytes (arrows) were distributed more evenly as very few Aβ-neuritic plaques were observed in this region. (E) Histological reconstruction of the hippocampal CA1 and the dentate gyrus showing differences in the localization and intensity of immunoreactivity of GFAP+ astrocytes. GFAP+ astrocytes are brown, the α7nAChRs are gray. Representative areas are displayed in the corresponding inserts (F-I). (F) In the CA1 alveus and stratum oriens, intensely stained small somata of GFAP+/α7nAChRs astrocytes and networks were observed. (G) Throughout the stratum pyramidale, large somata of GFAP+ astrocytes without α7nAChRs (arrows) were found dispersed throughout GFAP+ network. (H) Differences in the intensity of immunoreactivity and the number of GFAP+ astrocytes were detected in the stratum lacunosum-moleculare (upper layer, strong staining) and the molecular layer of the dentate gyrus (bottom layer, weak staining). (I) In the granular layer, weakly stained GFAP+ astrocytes and network (top layer) were accompanied by very strong stained α7nAChR/GFAP+ astrocytes (bottom layer, gray). Videocapture was performed with ×10 (A, E) and ×20 (B-D, F-I) objective lenses magnification.
Mentions: To relate the laminar [3H]-l-deprenyl autoradiography binding, the distribution of reactive astrocytes within different layers of the frontal cortex and hippocampal subregions in the single AD case was examined by immunohistochemistry with GFAP as a marker for astrocytosis. Differences in the localization and intensity of GFAP immunoreactive cells were found both within each region as well as between the regions (Figure 7). The distribution in the frontal cortex revealed a layer-specific localization of GFAP+ cells exhibiting heterogeneous morphologies (Figure 7A). A uniform distribution of reactive astrocytes with small somata and dense staining of GFAP+ neuropil was detected in the superficial (Figure 7B). In the deeper layers, GFAP+ astrocytic somata and densely stained neuropil were concentrated around Aβ plaques (Figure 7C). GFAP+ astrocytes were distributed more evenly in the cortical layer bordering the white matter (lamina VI), and very few Aβ plaques were observed in this region (Figure 7D).

Bottom Line: In vitro binding assays demonstrated increased [³H]-PIB (fibrillar Aβ) and [³H]-PK11195 (activated microglia) binding in the frontal cortex (FC) and hippocampus (HIP), as well as increased binding of [³H]-L-deprenyl (activated astrocytes) in the HIP, but a decreased [³H]-nicotine (α4β2 nicotinic acetylcholine receptor (nAChR)) binding in the FC of AD cases compared to age-matched controls.Although fewer Aβ plaques were observed in the HIP, some hippocampal GFAP+ astrocytes contained Aβ-positive (6 F/3D) granules within their somata.Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar Aβ, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum Floor-5, Stockholm S-14186, Sweden.

ABSTRACT

Background: The pathological features in Alzheimer's disease (AD) brain include the accumulation and deposition of β-amyloid (Aβ), 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 [³H]-PIB (fibrillar Aβ) and [³H]-PK11195 (activated microglia) binding in the frontal cortex (FC) and hippocampus (HIP), as well as increased binding of [³H]-L-deprenyl (activated astrocytes) in the HIP, but a decreased [³H]-nicotine (α4β2 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 [³H]-L-deprenyl, [³H]-PIB as well as [¹²⁵I]-α-bungarotoxin (α7 nAChRs) and [³H]-nicotine in hemisphere brain of a typical AD case. A clear lamination pattern was observed with high [³H]-PIB binding in all layers and [³H]-deprenyl in superficial layers of the FC. In contrast, [³H]-PIB showed low binding to fibrillar Aβ, but [³H]-deprenyl high binding to activated astrocytes throughout the HIP. The [³H]-PIB binding was also low and the [³H]-deprenyl binding high in all layers of the medial temporal gyrus and insular cortex in comparison to the frontal cortex. Low [³H]-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 α7 nAChR expressing GFAP+ astrocytes both in the vicinity and surrounding Aβ neuritic plaques in the FC and HIP. Although fewer Aβ plaques were observed in the HIP, some hippocampal GFAP+ astrocytes contained Aβ-positive (6 F/3D) granules within their somata.

Conclusions: Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar Aβ, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.

Show MeSH
Related in: MedlinePlus