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.
Highlights
The gradual accumulation of β-amyloid (Aβ) peptides in the brain, varying in size and state of aggregation, is suggested to play a central role in Alzheimer’s disease (AD), triggering a cascade of neurodegenerative changes in the brain
It is suggested that the inflammatory processes in AD may have contrasting roles where, for instance, activated glia eliminate Aβ plaques via phagocytosis but may initiate a proinflammatory cascade that results in the release of potentially neurotoxic substances such as cytokines, complement components, various free radicals, and nitric oxide, all of which may contribute to further neuronal dysfunction and cell death [16]
Comparison of binding levels for fibrillar amyloid, reactive astrocytes, and activated microglia in relation to α4β2 and α7 nicotinic receptors in AD and control brain Significantly higher binding levels of [3H]-PIB were measured both in the frontal cortex (P
Summary
The gradual accumulation of β-amyloid (Aβ) peptides in the brain, varying in size and state of aggregation, is suggested to play a central role in Alzheimer’s disease (AD), triggering a cascade of neurodegenerative changes in the brain These include neurofibrillary tangle formation, the activation and exacerbation of inflammatory processes, impairment of neurotransmitter signaling, and the perturbation of synaptic functions resulting in the death of neurons in brain areas associated with learning and memory [1,2]. AD-associated inflammation has been widely described by pathological examination of brain tissue from AD patients demonstrating abundant activated microglia in Aβ plaques and increased numbers of reactive astrocytes surrounding Aβ plaques [10,11,12,13,14,15] It is not clear whether the inflammatory response detected in postmortem brain was a cause or a consequence of disease progression. This information could aid the development of specific biomarkers to accurately chart disease progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
