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Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, r...

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Autores principales: Patthy, Ágoston, Murai, János, Hanics, János, Pintér, Anna, Zahola, Péter, Hökfelt, Tomas G. M., Harkany, Tibor, Alpár, Alán
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067882/
https://www.ncbi.nlm.nih.gov/pubmed/33917176
http://dx.doi.org/10.3390/jcm10081555
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author Patthy, Ágoston
Murai, János
Hanics, János
Pintér, Anna
Zahola, Péter
Hökfelt, Tomas G. M.
Harkany, Tibor
Alpár, Alán
author_facet Patthy, Ágoston
Murai, János
Hanics, János
Pintér, Anna
Zahola, Péter
Hökfelt, Tomas G. M.
Harkany, Tibor
Alpár, Alán
author_sort Patthy, Ágoston
collection PubMed
description Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.
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spelling pubmed-80678822021-04-25 Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease Patthy, Ágoston Murai, János Hanics, János Pintér, Anna Zahola, Péter Hökfelt, Tomas G. M. Harkany, Tibor Alpár, Alán J Clin Med Review Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years. MDPI 2021-04-07 /pmc/articles/PMC8067882/ /pubmed/33917176 http://dx.doi.org/10.3390/jcm10081555 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Patthy, Ágoston
Murai, János
Hanics, János
Pintér, Anna
Zahola, Péter
Hökfelt, Tomas G. M.
Harkany, Tibor
Alpár, Alán
Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease
title Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease
title_full Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease
title_fullStr Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease
title_full_unstemmed Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease
title_short Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease
title_sort neuropathology of the brainstem to mechanistically understand and to treat alzheimer’s disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067882/
https://www.ncbi.nlm.nih.gov/pubmed/33917176
http://dx.doi.org/10.3390/jcm10081555
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