[Gln22,Asn23]-beta-Amyloid (1-40), Dutch/Iowa double mutation

Product Name: [Gln22,Asn23]-beta-Amyloid (1-40), Dutch/Iowa double mutation

Sequence One Letter Code: DAEFRHDSGYEVHHQKLVFFAQNVGSNKGAIIGLMVGGVV

Sequence Three Letter Code: H-Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Gln-Asn-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-OH

Cas No: 374796-75-5

Chemical Formula:C194H297N55O56S

Molecular Weight: 4328.2

Purity: 95%

Form: Lyophilized

Storage Conditions: - 20 °C

Research Area: Alzheimer's Disease

Source / Species: human

Conjugation: Unconjugated

Code Nacres: NA.26

Application: β-Amyloid (1–40), Dutch/Iowa double mutant is a synthetic peptide containing the E22Q and D23N substitutions linked to autosomal dominant familial Alzheimer’s disease. Compared with single variants, this double mutant demonstrates accelerated fibrillogenesis and enhanced pathogenic potential, rapidly forming fibrils in solution. The peptide exhibits increased cytotoxicity in cultured cells and is frequently used as a robust aggregation model. It supports studies of amyloid assembly kinetics, vascular amyloidosis, mutation-driven structural changes, and mechanisms underlying hereditary Alzheimer’s disease progression.

Current Research: Familial forms of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) are frequently associated with point mutations in the amyloid-β (Aβ) sequence derived from amyloid precursor protein (APP). Among these, the Dutch (E22Q) and Iowa (D23N) substitutions occur within the central hydrophilic region of Aβ and are linked to autosomal dominant early-onset neurodegenerative disease. The β-Amyloid (1–40), Dutch/Iowa double mutant incorporates both E22Q and D23N substitutions within the Aβ1–40 backbone, generating a peptide with markedly altered aggregation behavior and pathogenic properties. This engineered variant serves as a powerful model for investigating mutation-driven amyloid assembly and vascular amyloidosis. Residues 22 and 23 are located within a critical turn region that influences β-sheet formation and intermolecular hydrogen bonding. Substitution of glutamic acid at position 22 with glutamine (E22Q) and aspartic acid at position 23 with asparagine (D23N) reduces local negative charge and modifies electrostatic interactions within the peptide. These changes destabilize soluble conformations while favoring intermolecular β-sheet stacking. As a result, the Dutch/Iowa double mutant demonstrates accelerated nucleation and fibrillogenesis compared with wild-type Aβ1–40 or single-mutant variants. In solution, the peptide rapidly transitions from monomeric or oligomeric species to β-sheet–rich fibrillar assemblies. Kinetic analyses using thioflavin T fluorescence assays consistently show shortened lag phases and increased aggregation rates for the double mutant. Circular dichroism spectroscopy confirms rapid acquisition of β-sheet secondary structure, while transmission electron microscopy reveals dense fibrillar networks forming at earlier time points relative to wild-type peptide. These properties make the Dutch/Iowa double mutant particularly suitable as a robust aggregation model for mechanistic and screening studies, where reproducible and rapid fibril formation is advantageous. Beyond aggregation kinetics, the double mutant exhibits enhanced cytotoxicity in cultured neuronal and endothelial cell systems. Oligomeric intermediates generated during early aggregation stages have been associated with membrane disruption, calcium dysregulation, oxidative stress, and mitochondrial impairment. The increased propensity of the Dutch/Iowa variant to form structured oligomers and fibrils correlates with heightened cellular stress responses and reduced viability. This phenotype supports investigation into structure–toxicity relationships and mechanisms by which familial mutations amplify amyloid-mediated injury. Importantly, both E22Q and D23N mutations are strongly associated with cerebral amyloid angiopathy, characterized by deposition of Aβ within cerebral blood vessel walls. The double mutant demonstrates increased affinity for vascular basement membrane components and enhanced stability of fibrillar assemblies, features that mirror pathological vascular amyloid deposition observed in affected individuals. Consequently, the peptide is widely used to model vascular amyloidosis and to study interactions between Aβ aggregates and endothelial or smooth muscle cells. These studies contribute to understanding how mutation-driven aggregation influences blood–brain barrier integrity and cerebrovascular dysfunction. Structural investigations using solid-state NMR and computational modeling indicate that substitutions at positions 22 and 23 alter β-strand alignment and intermolecular hydrogen-bonding patterns within fibrils. The reduction in electrostatic repulsion facilitates tighter packing and distinct fibril polymorphs. Comparative analyses between wild-type, single-mutant, and double-mutant peptides provide insight into how subtle sequence changes reshape the amyloid energy landscape and promote pathogenic assembly pathways. The Dutch/Iowa double mutant is also valuable for therapeutic evaluation. Because of its rapid and reproducible aggregation, it serves as a stringent test substrate for small-molecule aggregation inhibitors, metal chelators, and conformation-specific antibodies. Compounds that effectively modulate fibrillogenesis or reduce oligomer-associated toxicity in this system demonstrate potential for targeting aggressive familial forms of AD and CAA. In summary, β-Amyloid (1–40), Dutch/Iowa double mutant integrates two familial Alzheimer’s disease–linked substitutions that synergistically enhance fibril formation and cytotoxicity. Its accelerated aggregation kinetics, vascular amyloid relevance, and mutation-specific structural features make it a critical research tool for studying hereditary amyloid disorders. By enabling detailed analysis of assembly mechanisms, mutation-induced conformational changes, and pathogenic signaling, this peptide advances understanding of genetic contributions to Alzheimer’s disease progression and supports development of targeted therapeutic strategies.