Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala→Gly mutation

Cras, Patrick; Hendriks, Lydia; Ceuterick, C.; Duijn, Cornelia M. van; Stefanko, S. Z.; Hofman, Albert; Kros, J. M.; Broeckhoven, Christine Van; Martin, Jean‐Jacques; Harskamp, F. van

doi:10.1007/s004010050892

Cited by 97 publications

(73 citation statements)

References 37 publications

(37 reference statements)

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“…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: 65%

“…Although BACE2 is expressed at relatively low levels in the cortex, a shift in its activity from limiting to producing amyloidogenic A␤ fragments (i.e., starting at Asp-1) could contribute to the large senile plaques observed in these patients (11). High expression of BACE2 in the kidney, placenta, and heart is consistent with the presence of BACE2 in the vasculature, and a role for BACE2 in the angiopathy and cerebral hemorrhages observed in the Flemish patients (8).…”

Section: Discussionmentioning

confidence: 99%

“…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: 93%

“…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).…”

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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.

376

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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Section: Bace2 Generates Two C-terminal Fragments Of Appsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Bace2 Generates Two C-terminal Fragments Of Appmentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

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.

376

346

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

Basun¹,

Bogdanović²,

Ingelsson³

et al. 2008

Arch Neurol

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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

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Hereditary Cerebral Hemorrhage With Amyloidosis Associated With the E693K Mutation of APP

Bugiani¹,

Giaccone²,

Rossi³

et al. 2010

Arch Neurol

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To report the clinical, genetic, neuroimaging, and neuropathologic studies of patients with the hereditary cerebral hemorrhage with amyloidosis linked to the APP E693K mutation. Design: Case series. Clinical details and laboratory results were collected by direct evaluation and previous medical records. DNA analysis was carried out in several affected subjects and healthy individuals. Neuropathologic examination was performed in 2 subjects.

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Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala→Gly mutation

Cited by 97 publications

References 37 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

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

Hereditary Cerebral Hemorrhage With Amyloidosis Associated With the E693K Mutation of APP

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