Amyloid β Protein Precursor Gene and Hereditary Cerebral Hemorrhage with Amyloidosis (Dutch)

Broeckhoven, Christine Van; Haan, Joost; Bakker, Egbert; Hardy, John; Hul, Wim Van; Wehnert, A.; Vlis, Maria Vegter-van der; Roos, Raymund A.C.

doi:10.1126/science.1971458

Cited by 429 publications

(226 citation statements)

References 28 publications

(19 reference statements)

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“…Familial forms of AD result from a single point mutation in A␤ peptides and are characterized by early onset and aggravated severity. In this article, we focus on the Dutch AD type, which is associated with the E22Q substitution (21). Numerous in vitro experiments have shown that A␤ peptides with the Dutch mutation aggregate more readily than their WT A␤ counterparts, in addition to exhibiting increased cytotoxic activity (1,3,22).…”

Section: Discussionmentioning

confidence: 99%

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Baumketner

Krone

Shea³

2008

Proc. Natl. Acad. Sci. U.S.A.

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Amyloid fibrils, large ordered aggregates of amyloid ␤ proteins (A␤), are clinical hallmarks of Alzheimer's disease (AD). The aggregation properties of amyloid ␤ proteins can be strongly affected by singlepoint mutations at positions 22 and 23. The Dutch mutation involves a substitution at position 22 (E22Q) and leads to increased deposition rates of the A␤E22Q peptide onto preseeded fibrils. We investigate the effect of the E22Q mutation on two key regions involved in the folding and aggregation of the A␤ peptide through replica exchange molecular dynamics simulations of the 15-28 fragment of the A␤ peptide. The A␤15-28 peptide encompasses the 22-28 region that constitutes the most structured part of the A␤ peptide (the E22-K28 bend), as well as the central hydrophobic cluster (CHC) (segment 17-21), the primary docking site for A␤ monomers depositing onto fibrils. Our simulations show that the 22-28 bend is preserved in the A␤(15-28) peptide and that the CHC, which is mostly unstructured, interacts with this bend region. The E22Q mutation does not affect the structure of the bend but weakens the interactions between the CHC and the bend. This leads to an increased population of ␤-structure in the CHC. Our analysis of the fibril elongation reaction reveals that the CHC adopts a ␤-strand conformation in the transition state ensemble, and that the E22Q mutation increases aggregation rates by lowering the barrier for A␤ monomer deposition onto a fibril. Thermodynamic signatures of this enhanced fibrillization process from our simulations are in good agreement with experimental observations. Alzheimer's disease ͉ explicit water ͉ familial type ͉ molecular dynamics simulations ͉ replica exchange T he presence of amyloid fibrils in the brain is a clinical hallmark of Alzheimer's disease (AD). The fibrils consist of large ordered aggregates of amyloid-␤ (A␤) peptides, proteolytic by-products of the enzymatic cleavage of the Alzheimer amyloid precursor protein (APP). AD can be sporadic (occurring in elderly patients and characterized by a slow progression) or familial (a hereditary form characterized by early onset of the disease and aggravated severity). The majority of familial forms of AD involve single-point mutations in the 22-23 segment of the A␤ peptide. The focus of this work is on the Dutch form of AD, which involves a mutation encoded by a point substitution G to C at codon 693 of the amyloid precursor protein (APP). The result is the production of an A␤ peptide in which residue E22 is mutated to Q (E22Q mutation). Patients who have this mutation are at risk of developing cerebral amyloid angiopathy that typically leads to cerebral hemorrhage and stroke. Many in vitro experiments show that the A␤E22Q peptide aggregates much more readily than its wild-type (WT) counterpart (1-3). As a free monomer in solution, the WT A␤ peptide is for the most part unstructured with residual structure observed locally in a few regions of the primary sequence (4). The A␤ peptide can populate a variety of oligomeric species, some...

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Section: Discussionmentioning

confidence: 99%

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Baumketner

Krone

Shea³

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Two additional peaks corresponding to A␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and A␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were also observed, although they were substantially smaller than the A␤(1-10) peak. When A␤(1-28) was incubated with BACE2, pronounced peaks corresponding to A␤(1-19) and A␤(1-20) were observed, as was A␤(21-28), the C-terminal counterpart of A␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)…”

Section: Bace2 Generates Two C-terminal Fragments Of Appmentioning

confidence: 99%

“…The same peptide incubated with BACE1 produced a strong peak corresponding to the A␤(1-10) and a peak corresponding to A␤ (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) consistent with the observed internal A␤ cleavage product after Tyr-10 (15). Two additional peaks corresponding to A␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and A␤ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)…”

Section: Bace2 Generates Two C-terminal Fragments Of Appmentioning

confidence: 99%

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BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein

Farzan

Schnitzler

Vasilieva

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

380

346

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Production of amyloid-␤ protein (A␤) is initiated by a ␤-secretase that cleaves the A␤ precursor protein (APP) at the N terminus of A␤ (the ␤ site). A recently identified aspartyl protease, BACE, cleaves the ␤ site and at residue 11 within the A␤ region of APP. Here we show that BACE2, a BACE homolog, cleaves at the ␤ site and more efficiently at a different site within A␤. The Flemish missense mutation of APP, implicated in a form of familial Alzheimer's disease, is adjacent to this latter site and markedly increases A␤ production by BACE2 but not by BACE. BACE and BACE2 respond identically to conservative ␤-site mutations, and alteration of a common active site Arg inhibits ␤-site cleavage but not cleavage within A␤ by both enzymes. These data suggest that BACE2 contributes to A␤ production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous.T he amyloid-␤ protein (A␤) is the principal component of the senile plaques characteristic of Alzheimer's disease (AD), and multiple lines of evidence have implicated cerebral accumulation of A␤ in AD pathogenesis (1, 2). A␤ is produced from the A␤ precursor protein (APP) by two proteolytic events. A ␤-secretase activity cleaves APP at the N terminus of A␤ (␤ site) between amino acids Met-671 and Asp-672 (using the numbering of the 770-aa isoform of APP). Cleavage at the ␤ site yields a membrane-associated APP fragment of 99 aa (C99). A second site within the transmembrane domain of C99 (␥ site) can then be cleaved by a ␥-secretase to release A␤, a peptide of 39-42 aa. APP can alternatively be cleaved within its A␤ region, predominately at the ␣-secretase cleavage site of APP, to produce a C-terminal APP fragment of 83 aa (C83), which can also be further cleaved by ␥-secretase to produce a small secreted peptide, p3.A number of missense mutations in APP have been implicated in forms of early-onset familial AD. All of these are at or near one of the canonical cleavage sites of APP. Thus, the Swedish double mutation (K670N͞M671L) is immediately adjacent to the ␤-cleavage site and increases the efficiency of ␤-secretase activity, resulting in more total A␤ (3). Any of three mutations at APP residue 717, near the ␥ site, increases the proportion of a more amyloidogenic 42-aa form of A␤ [A␤(1-42)] relative to the more common 40-residue form [A(␤1-40)] (4-7).Two additional mutations of APP have been described which are close but not adjacent to the ␣ site. A mutation (A692G, A␤ residue 21) in a Flemish family and a mutation (E693Q, A␤ residue 22) in a Dutch family each have been implicated in distinct forms of familial AD (8-10). The Flemish mutation, in particular, presents as a syndrome of repetitive intracerebral hemorrhages or as an AD-type dementia. The neuropathological findings include senile plaques in the cortex and hippocampus, and usually multiple amyloid deposits in the walls of cerebral microvessels (8,11,12).Recently, a membrane-associated aspartyl protease, B...

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“…Several genetic mutations within the A␤ peptide sequence have been reported, including the Flemish (A21G) (27), Italian (E22K) (28), Dutch (E22Q) (29,30), Arctic (E22G) (31), and Iowa (D23N) (32,33) mutations. Clinically, these mutations lead to AD-like symptoms secondary to intracerebral hemorrhage, although in some cases a progressive dementia is present in the absence of stroke.…”

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confidence: 99%

Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

Dahlgren

Manelli

Stine

et al. 2002

Journal of Biological Chemistry

1,348

1,288

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Genetic evidence predicts a causative role for amyloid-␤ (A␤) in Alzheimer's disease. Recent debate has focused on whether fibrils (amyloid) or soluble oligomers of A␤ are the active species that contribute to neurodegeneration and dementia. We developed two aggregation protocols for the consistent production of stable oligomeric or fibrillar preparations of A␤-(1-42). Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and ϳ40-fold more than unaggregated peptide, with oligomeric A␤-(1-42)-induced inhibition significant at 10 nM. Under A␤-(1-42) oligomer-and fibril-forming conditions, A␤-(1-40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than preparations of A␤-(1-42). We applied the aggregation protocols developed for wild type A␤-(1-42) to A␤-(1-42) with the Dutch (E22Q) or Arctic (E22G) mutations. Oligomeric preparations of the mutations exhibited extensive protofibril and fibril formation, respectively, but were not consistently different from wild type A␤-(1-42) in terms of inhibition of neuronal viability. However, fibrillar preparations of the mutants appeared larger and induced significantly more inhibition of neuronal viability than wild type A␤-(1-42) fibril preparations. These data demonstrate that protocols developed to produce oligomeric and fibrillar A␤-(1-42) are useful in distinguishing the structural and functional differences between A␤-(1-42) and A␤-(1-40) and genetic mutations of A␤-(1-42). Amyloid-␤ (A␤)1 is derived by the proteolytic processing of amyloid precursor protein (APP), resulting in a peptide predominantly 40 or 42 amino acids in length. Mutations in APP and the presenilins that increase the amount of A␤-(1-42) cause AD (for review, see Ref. 1). Historically, the "amyloid cascade" hypothesis has defined the fibrillization of A␤ into amyloid deposits, a pathologic hallmark of AD, as a toxic gain of function (2). That A␤-(1-42) is more fibrillogenic than A␤-(1-40) fits well with this hypothesis. However, amyloid plaques do not always correlate in number, tempo, or distribution with neurodegeneration or clinical dementia. Thus, recent debate within the AD community has focused on whether fibrillar (amyloid) or soluble oligomers of A␤ are the active species of the peptide that ultimately cause the synaptic loss and dementia associated with AD (3-7). In vivo, small, stable oligomers of A␤-(1-42) have been isolated from brain, plasma, and cerebrospinal fluid (8 -10) and correlate with the severity of neurodegeneration in AD (11, 12). Thus, although genetic evidence predicts that A␤ is a causative factor in AD, the role of fibrillar and oligomeric A␤ in the pathogenesis of AD remains unclear.Initial in vitro studies suggested that A␤-induced neurotoxicity required the peptide to adopt a fibrillar aggregation state, with unaggregated peptide at low doses actually exhibiting neurotrophic effects (13)(14)(15)(16)(17)(18)). Recent studies demonstrate that non-fibrillar structures, including oligomers and ...

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Amyloid β Protein Precursor Gene and Hereditary Cerebral Hemorrhage with Amyloidosis (Dutch)

Cited by 429 publications

References 28 publications

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein

Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

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