The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease
Intraneuronal amyloid β (Aβ) oligomer accumulation precedes the appearance of amyloid plaques or neurofibrillary tangles and is neurotoxic. In Alzheimer’s disease (AD)-affected brains, intraneuronal Aβ oligomers can derive from Aβ peptide production within the neuron and, also, from vicinal neurons...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/9/4976 |
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| author | Joana Poejo Jairo Salazar Ana M. Mata Carlos Gutierrez-Merino |
| author_facet | Joana Poejo Jairo Salazar Ana M. Mata Carlos Gutierrez-Merino |
| author_sort | Joana Poejo |
| collection | DOAJ |
| description | Intraneuronal amyloid β (Aβ) oligomer accumulation precedes the appearance of amyloid plaques or neurofibrillary tangles and is neurotoxic. In Alzheimer’s disease (AD)-affected brains, intraneuronal Aβ oligomers can derive from Aβ peptide production within the neuron and, also, from vicinal neurons or reactive glial cells. Calcium homeostasis dysregulation and neuronal excitability alterations are widely accepted to play a key role in Aβ neurotoxicity in AD. However, the identification of primary Aβ-target proteins, in which functional impairment initiating cytosolic calcium homeostasis dysregulation and the critical point of no return are still pending issues. The micromolar concentration of calmodulin (CaM) in neurons and its high affinity for neurotoxic Aβ peptides (dissociation constant ≈ 1 nM) highlight a novel function of CaM, i.e., the buffering of free Aβ concentrations in the low nanomolar range. In turn, the concentration of Aβ-CaM complexes within neurons will increase as a function of time after the induction of Aβ production, and free Aβ will rise sharply when accumulated Aβ exceeds all available CaM. Thus, Aβ-CaM complexation could also play a major role in neuronal calcium signaling mediated by calmodulin-binding proteins by Aβ; a point that has been overlooked until now. In this review, we address the implications of Aβ-CaM complexation in the formation of neurotoxic Aβ oligomers, in the alteration of intracellular calcium homeostasis induced by Aβ, and of dysregulation of the calcium-dependent neuronal activity and excitability induced by Aβ. |
| first_indexed | 2024-03-10T11:38:11Z |
| format | Article |
| id | doaj.art-101a01d2571e4c0fa3144d7bc3be84c5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:38:11Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-101a01d2571e4c0fa3144d7bc3be84c52023-11-21T18:40:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01229497610.3390/ijms22094976The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s DiseaseJoana Poejo0Jairo Salazar1Ana M. Mata2Carlos Gutierrez-Merino3Instituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, SpainInstituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, SpainInstituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, SpainInstituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, SpainIntraneuronal amyloid β (Aβ) oligomer accumulation precedes the appearance of amyloid plaques or neurofibrillary tangles and is neurotoxic. In Alzheimer’s disease (AD)-affected brains, intraneuronal Aβ oligomers can derive from Aβ peptide production within the neuron and, also, from vicinal neurons or reactive glial cells. Calcium homeostasis dysregulation and neuronal excitability alterations are widely accepted to play a key role in Aβ neurotoxicity in AD. However, the identification of primary Aβ-target proteins, in which functional impairment initiating cytosolic calcium homeostasis dysregulation and the critical point of no return are still pending issues. The micromolar concentration of calmodulin (CaM) in neurons and its high affinity for neurotoxic Aβ peptides (dissociation constant ≈ 1 nM) highlight a novel function of CaM, i.e., the buffering of free Aβ concentrations in the low nanomolar range. In turn, the concentration of Aβ-CaM complexes within neurons will increase as a function of time after the induction of Aβ production, and free Aβ will rise sharply when accumulated Aβ exceeds all available CaM. Thus, Aβ-CaM complexation could also play a major role in neuronal calcium signaling mediated by calmodulin-binding proteins by Aβ; a point that has been overlooked until now. In this review, we address the implications of Aβ-CaM complexation in the formation of neurotoxic Aβ oligomers, in the alteration of intracellular calcium homeostasis induced by Aβ, and of dysregulation of the calcium-dependent neuronal activity and excitability induced by Aβ.https://www.mdpi.com/1422-0067/22/9/4976amyloid βcalmodulinneuronsAlzheimer’s diseasecalmodulin-binding proteinsintracellular calcium dysregulation |
| spellingShingle | Joana Poejo Jairo Salazar Ana M. Mata Carlos Gutierrez-Merino The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease International Journal of Molecular Sciences amyloid β calmodulin neurons Alzheimer’s disease calmodulin-binding proteins intracellular calcium dysregulation |
| title | The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease |
| title_full | The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease |
| title_fullStr | The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease |
| title_full_unstemmed | The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease |
| title_short | The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer’s Disease |
| title_sort | relevance of amyloid β calmodulin complexation in neurons and brain degeneration in alzheimer s disease |
| topic | amyloid β calmodulin neurons Alzheimer’s disease calmodulin-binding proteins intracellular calcium dysregulation |
| url | https://www.mdpi.com/1422-0067/22/9/4976 |
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