Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch Type (HCHWA‐D): I ‐ A Review of Clinical, Radiologic and Genetic Aspects

Bornebroek, M.; Haan, Joost; Maat-Schieman, M. L. C.; Duinen, Sjoerd G. van; Roos, Raymund A.C.

doi:10.1111/j.1750-3639.1996.tb00793.x

Cited by 113 publications

(75 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3, peptide incubated with precipitates of mock-transfected cells was not cleaved, and a strong peak of 3261.5 corresponding to A␤(1-28) was observed. 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)…”

Section: Bace2 Generates Two C-terminal Fragments Of Appsupporting

confidence: 55%

“…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 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, BACE (also called ␤-secretase or Asp2) has been shown to exhibit properties expected of a ␤-secretase (13-16). This enzyme cleaves APP at its ␤ site and between Tyr-10 and Glu-11 of the A␤ region with comparable efficiency (15).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

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...

show abstract

Section: Bace2 Generates Two C-terminal Fragments Of Appsupporting

confidence: 55%

Section: Bace2 Generates Two C-terminal Fragments Of Appmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

“…The main symptoms are (recurrent) hemorrhagic stroke and dementia in the 5th or 6th decade of life [96] . About two thirds of patients with HCHWA-D experience fatal ICH, and the remaining one third present with vascular dementia.…”

Section: Hemorrhagic Strokementioning

confidence: 99%

Genetics of stroke

Guo

Liu

2010

Acta Pharmacol Sin

View full text Add to dashboard Cite

Stroke is the second most common cause of death and the most common cause of disability in developed countries. Stroke is a multifactorial disease caused by a combination of environmental and genetic factors. Numerous epidemiologic studies have documented a significant genetic component in the occurrence of strokes. Genes encoding products involved in lipid metabolism, thrombosis, and inflammation are believed to be potential genetic factors for stroke. Although a large group of candidate genes have been studied, most of the epidemiological results are conflicting. Studies of stroke as a monogenic disease have made huge progress, and animal models serve as an indispensable tool to dissect the complex genetics of stroke. In the present review, we provide insight into the role of in vivo stroke models for the study of stroke genetics.

show abstract

Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease

Basun¹,

Bogdanović²,

Ingelsson³

et al. 2008

Arch Neurol

View full text Add to dashboard Cite

Background: A majority of mutations within the ␤amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-␤-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease.Objective: To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation.Design, Setting, and Participants: Affected and nonaffected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. Results:The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in

show abstract

Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch Type (HCHWA‐D): I ‐ A Review of Clinical, Radiologic and Genetic Aspects

Cited by 113 publications

References 41 publications

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

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

Genetics of stroke

Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease

Contact Info

Product

Resources

About