The AβA2V paradigm: From molecular insights to therapeutic strategies in Alzheimer’s disease and primary tauopathies

• Published in: Pharmacological research Vol. 211; p. 107563
• Main Authors: Diomede, Luisa, Conz, Andrea, Mosconi, Michele, Stoilova, Tatiana, Paloni, Matteo, Salvalaglio, Matteo, Cagnotto, Alfredo, Colombo, Laura, Catania, Marcella, Di Fede, Giuseppe, Tagliavini, Fabrizio, Salmona, Mario
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2025; Elsevier
• Subjects: A673V mutation; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid-β plaques; Animals; Aβ1–6A2V(D) peptide; Familial AD; Humans; Mutation; Neuroprotection; Neuroprotective Agents - therapeutic use; Protein aggregation; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - drug therapy; Tauopathies - genetics; Tauopathies - metabolism; Tauopathies - therapy; Therapeutic strategies; Amyloid-β plaques; APP; Neuroprotection; Protein aggregation; NT; Aβ1–28A2V; AFM; LTP; Aβ1–42WT; Aβ1–42A2T; Cs; Aβ; Aβ1–28WT; SPR; MD; TBI; WT; Alzheimer's disease; AD; Aβ42; A673V mutation; Aβ40; Therapeutic strategies; FAD; Aβ1–6A2V(D) peptide; REMD; Amyloid precursor protein; BACE1; NOR; CT; Tau protein; Familial AD; AβA2V; CHC; Aβ1–6(A2V)(D) peptide
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2024.107563

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. [Display omitted] •A673V mutation offers insight into Alzheimer's pathogenesis and amyloid β aggregation.•Aβ1–6A2V(D) shows neuroprotective activity by inhibiting amyloid β fibril formation.•Aβ1–6A2V(D) reduces amyloid β toxicity and slows cognitive decline in preclinical models.•AβA2V-based therapy is cost-effective and can be administered intranasally for higher patient compliance.