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

Abstract

BackgroundThe 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.ResultsIn 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.ConclusionsAstrocytosis 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.

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

“…The biochemical quantification of GFAP with ELISA confirmed the results obtained with immunohistochemistry and indicated that increased GFAP levels were a consequence of, or at least mirrored, the Aβ accumulation. These results are also supported by the previous studies in APP swe mice and on post mortem human brain tissue [30,42]. Another preclinical study, conducted in APP/PS1 mice, focusing on GABA function reported low degree of co- localization of MAO-B and GFAP [43].…”

Molecular Imaging in Sporadic Alzheimer's Disease Populations and Those Genetically at Risk

“…Astrocytosis shows a spatial and temporal pattern different from both fibrillar amyloid and cerebral glucose metabolism [14]. In vitro autoradiography studies with 3 H-deprenyl show higher labeling in the superficial layers in comparison to binding in the deeper layers of the frontal AD cortices [15]. This is in agreement with earlier findings of gliosis in different cortical layers [16].…”

“…This is in agreement with earlier findings of gliosis in different cortical layers [16]. High binding of 3 H-deprenyl is found in all hippocampal subregions [15]. The fibrillar Aβ 3 H-PIB binding is high in all frontal cortical layers and low in the hippocampus [15].…”

“…High binding of 3 H-deprenyl is found in all hippocampal subregions [15]. The fibrillar Aβ 3 H-PIB binding is high in all frontal cortical layers and low in the hippocampus [15]. The observed different laminar distribution of astrocytosis and fibrillar Aβ might therefore indicate parallel processes with a different time course and regional variability.…”

Lynx1 and Aβ1–42 bind competitively to multiple nicotinic acetylcholine receptor subtypes

“…Combined with the observation that cholinergic neurons degenerate and nAChR levels are decreased in AD (Auld et al, 2002;Marutle et al, 2013;Okada et al, 2013), the above results suggest that the interaction between nAChRs and Aβ 1-42 affects cognitive function and may be involved in the pathophysiology of Alzheimer's disease.…”