The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies
Alzheimer’s disease, the leading cause of dementia globally, represents an unresolved clinical challenge due to its complex pathogenesis and the absence of effective treatments. Considering the multifactorial etiology of the disease, mainly characterized by the accumulation of amyloid β plaques and...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824005085 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841553832678522880 |
|---|---|
| author | Luisa Diomede Andrea Conz Michele Mosconi Tatiana Stoilova Matteo Paloni Matteo Salvalaglio Alfredo Cagnotto Laura Colombo Marcella Catania Giuseppe Di Fede Fabrizio Tagliavini Mario Salmona |
| author_facet | Luisa Diomede Andrea Conz Michele Mosconi Tatiana Stoilova Matteo Paloni Matteo Salvalaglio Alfredo Cagnotto Laura Colombo Marcella Catania Giuseppe Di Fede Fabrizio Tagliavini Mario Salmona |
| author_sort | Luisa Diomede |
| collection | DOAJ |
| description | Alzheimer’s disease, the leading cause of dementia globally, represents an unresolved clinical challenge due to its complex pathogenesis and the absence of effective treatments. Considering the multifactorial etiology of the disease, mainly characterized by the accumulation of amyloid β plaques and neurofibrillary tangles of tau protein, we discuss the A673V mutation in the gene coding for the amyloid precursor protein, which is associated with the familial form of Alzheimer’s disease in a homozygous state. The mutation offers new insights into the molecular mechanisms of the disease, particularly regarding the contrasting roles of the A2V and A2T mutations in amyloid β peptide aggregation and toxicity. This review aims to describe relevant studies on A2V-mutated variants of the amyloid β peptide, revealing a protective effect against amyloid-β and tau pathology. Notably, special attention is given to the development of the peptide Aβ1–6A2V(D), which shows significant neuroprotective activity through inhibition of the assembly of amyloid β into amyloid fibrils. The therapeutic potential of this peptide emerges from its ability to reduce amyloid β-induced toxicity, with promising results from studies in human neuroblastoma cells and transgenic animal models. |
| format | Article |
| id | doaj-art-91278a28665040dcb53b0c5f6fe18c23 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-91278a28665040dcb53b0c5f6fe18c232025-01-09T06:13:06ZengElsevierPharmacological Research1096-11862025-01-01211107563The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathiesLuisa Diomede0Andrea Conz1Michele Mosconi2Tatiana Stoilova3Matteo Paloni4Matteo Salvalaglio5Alfredo Cagnotto6Laura Colombo7Marcella Catania8Giuseppe Di Fede9Fabrizio Tagliavini10Mario Salmona11Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, Italy; Corresponding authors.Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyDepartment of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyDepartment of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyThomas Young Centre and Department of Chemical Engineering, University College London, London WC1E 7JE, UKThomas Young Centre and Department of Chemical Engineering, University College London, London WC1E 7JE, UKDepartment of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyDepartment of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, ItalyUnit of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, ItalyUnit of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, ItalyUnit of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, ItalyDepartment of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, Italy; Corresponding authors.Alzheimer’s disease, the leading cause of dementia globally, represents an unresolved clinical challenge due to its complex pathogenesis and the absence of effective treatments. Considering the multifactorial etiology of the disease, mainly characterized by the accumulation of amyloid β plaques and neurofibrillary tangles of tau protein, we discuss the A673V mutation in the gene coding for the amyloid precursor protein, which is associated with the familial form of Alzheimer’s disease in a homozygous state. The mutation offers new insights into the molecular mechanisms of the disease, particularly regarding the contrasting roles of the A2V and A2T mutations in amyloid β peptide aggregation and toxicity. This review aims to describe relevant studies on A2V-mutated variants of the amyloid β peptide, revealing a protective effect against amyloid-β and tau pathology. Notably, special attention is given to the development of the peptide Aβ1–6A2V(D), which shows significant neuroprotective activity through inhibition of the assembly of amyloid β into amyloid fibrils. The therapeutic potential of this peptide emerges from its ability to reduce amyloid β-induced toxicity, with promising results from studies in human neuroblastoma cells and transgenic animal models.http://www.sciencedirect.com/science/article/pii/S1043661824005085Alzheimer's diseaseAmyloid-β plaquesTau proteinA673V mutationFamilial ADAβ1–6A2V(D) peptide |
| spellingShingle | Luisa Diomede Andrea Conz Michele Mosconi Tatiana Stoilova Matteo Paloni Matteo Salvalaglio Alfredo Cagnotto Laura Colombo Marcella Catania Giuseppe Di Fede Fabrizio Tagliavini Mario Salmona The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies Pharmacological Research Alzheimer's disease Amyloid-β plaques Tau protein A673V mutation Familial AD Aβ1–6A2V(D) peptide |
| title | The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies |
| title_full | The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies |
| title_fullStr | The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies |
| title_full_unstemmed | The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies |
| title_short | The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies |
| title_sort | aβa2v paradigm from molecular insights to therapeutic strategies in alzheimer s disease and primary tauopathies |
| topic | Alzheimer's disease Amyloid-β plaques Tau protein A673V mutation Familial AD Aβ1–6A2V(D) peptide |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824005085 |
| work_keys_str_mv | AT luisadiomede theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT andreaconz theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT michelemosconi theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT tatianastoilova theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT matteopaloni theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT matteosalvalaglio theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT alfredocagnotto theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT lauracolombo theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT marcellacatania theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT giuseppedifede theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT fabriziotagliavini theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT mariosalmona theaba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT luisadiomede aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT andreaconz aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT michelemosconi aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT tatianastoilova aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT matteopaloni aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT matteosalvalaglio aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT alfredocagnotto aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT lauracolombo aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT marcellacatania aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT giuseppedifede aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT fabriziotagliavini aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies AT mariosalmona aba2vparadigmfrommolecularinsightstotherapeuticstrategiesinalzheimersdiseaseandprimarytauopathies |