Modeling familial British and Danish dementia

Garringer, Holly J.; Murrell, Jill R.; D’Adamio, Luciano; Ghetti, Bernardino; Vidal, Rubén

doi:10.1007/s00429-009-0221-9

Cited by 46 publications

(43 citation statements)

References 54 publications

(112 reference statements)

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“…In normal individuals, BRI2 is synthesized as an immature type-II membrane protein (imBRI2) that is cleaved at the C-terminus by a pro-protein convertase to produce mature BRI2 (mBRI2) and a 23aa soluble C-terminal fragment (Bri23)[2]. However, in FDD patients, a longer C-terminal fragment, the ADan peptide [1], is generated from the Danish mutant protein (BRI2-ADan), which has amyloidogenic properties.…”

Section: Introductionmentioning

confidence: 99%

Increased AβPP Processing in Familial Danish Dementia Patients

Matsuda

Tamayev

D’Adamio

2011

JAD

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An autosomal dominant mutation in the BRI2/ITM2B gene causes Familial Danish Dementia (FDD). We have generated a mouse model of FDD, called FDDKI, genetically congruous to the human disease. These mice carry one mutant and one wild type Bri2/Itm2b allele, like FDD patients. Analysis of FDDKI mice and samples from human patients has shown that the Danish mutation causes loss of Bri2 protein. FDDKI mice show synaptic plasticity and memory impairments. BRI2 is a physiological interactor of amyloid-β protein precursor (AβPP), a gene associated with Alzheimer’s disease, which inhibits processing of AβPP. AβPP/Bri2 complexes are reduced in synaptic membranes of FDDKI mice. Consequently, AβPP metabolites derived from processing of AβPP by β-, α-, and γ-secretases are increased in Danish dementia mice. AβPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AβPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AβPP and BRI2 functionally interact. Here, we have investigated whether AβPP processing is altered in FDD patients’ brain samples. We find that the levels of several AβPP metabolites, including Aβ, are significantly increased in the brain sample derived from an FDD patient. Our data are consistent with the findings in FDDKI mice, and support the hypothesis that the neurological effects of the Danish form of BRI2 are caused by toxic AβPP metabolites, suggesting that Familial Danish and Alzheimer’s dementias share common pathogenic mechanisms.

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Section: Introductionmentioning

confidence: 99%

Increased AβPP Processing in Familial Danish Dementia Patients

Matsuda

Tamayev

D’Adamio

2011

JAD

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“…In contrast, mutations in APP and in genes that regulate APP processing, such as PSENs and BRI2/ITM2B, cause familial dementias (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). APP is cleaved by ␤-secretase/BACE1 into a soluble ectodomain (soluble APP␤) and the COOH-terminal fragment ␤-CTF.…”

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confidence: 99%

Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

Rice

Rajadhyaksha

et al. 2016

Journal of Biological Chemistry

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The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH 2 terminus of the ACR, and CRL4 CRBN , which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn. APP shares essential functions with APP-like protein-2 (APLP2) but not APP-like protein-1 (APLP1 The ACR facilitated in vitro ubiquitination of presynaptic proteins that regulate exocytosis, suggesting a mechanism by which APP tunes transmitter release. Other dementia-related proteins, namely Tau and apoE, interact with and are ubiquitinated via the ACR in vitro. This, and the evidence that CRBN and CUL4B are linked to intellectual disability, prompts us to hypothesize a pathogenic mechanism, in which APP acts as a modulator of E3 ubiquitin-protein ligase(s), shared by distinct neuronal disorders. The well described accumulation of ubiquitinated protein inclusions in neurodegenerative diseases and the link between the ubiquitin-proteasome system and neurodegeneration make this concept plausible. Processing of APP2 plays an important role in the central nervous system. A polymorphism in APP that reduces APP processing protects from sporadic Alzheimer disease (AD) (1). In contrast, mutations in APP and in genes that regulate APP processing, such as PSENs and BRI2/ITM2B, cause familial dementias (2-12). APP is cleaved by ␤-secretase/BACE1 into a soluble ectodomain (soluble APP␤) and the COOH-terminal fragment ␤-CTF. Alternatively, ␣-secretase cleaves APP into soluble APP␣ and a shorter COOH-terminal fragment, ␣-CTF. ␤-CTF and ␣-CTF can be cleaved by ␥-secretase to produce A␤ and the APP intracellular domain (AID) or P3 and AID, respectively (13-17). AID contains the ACR plus a few amino acids derived from the trans-membrane region of APP. AID is released in the cytosol upon production. Another processing pathway involves cleavage of APP in the ACR by caspase-6, -3, and -8 (18 -24). Sequential ␥-secretase/caspase processing can potentially generate the NH 2 -and COOH-terminal cytosolic peptides JCasp and Ccas (23,24).In vivo studies have identified an essential role for the ACR in the patterning of neuromuscular junction and survival and in synaptic transmission (25)(26)(27)(28)(29). Other studies have suggested that release of AID modulates apoptosis, gene transcription, and Ca 2ϩ homeostasis (23, 30 -40). The caspase-derived APP fragments Ccas and JCasp also possess toxic activities (22)(23)(24). Overall, these data indicate that the ACR is functionally important in vivo.APP belongs to a protein family that includes APLP1 and APLP2. APLP1 and APLP2 are processed like APP (41-45) and release intracellular peptides, called ALID1 and ALID2, respectiv...

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“…Applications of mutant-mouse variants have provided great inroads to the further staging of AD [e.g., familial British dementia (FBD) and familial Danish dementia (FDD) are two autosomal dominant neurodegenerative diseases caused by mutations in the BRI (2) gene]. Garringer et al (2009) developed transgenic mice that express wild-type and mutant forms of the BRI(2) protein, with Bri (2) knock-in mutant mice, and Bri (2) gene knock-out mice showing extensive CAA, parenchymal amyloid deposition, and neuroinflammation.…”

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confidence: 99%

Staging Neurological Disorders: Expressions of Cognitive and Motor Disorder

Archer

Kostrzewa

2009

Neurotox Res

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In neurologic disorders, there are progressive losses in regional brain structural integrity, circuitry, and neuronal process that threaten individuals' ability to express functional capacity at several levels of severity. The classification of (a) patients on the basis of diagnosis, risk prognosis, and intervention outcome forms the basis of clinical staging and (b) laboratory animals on the basis of animal model of brain disorder, extent of insult and dysfunctional expression, provides the components for the clinical staging and preclinical staging, respectively, of the disease state with certain associated epidemiological, biological, and genetic characteristics. The investigation of epigenetics and biomarkers is intrinsic to any analysis of the progressive nature of the neurogenerative disorders, in the present account disorders relating to Alzheimer's disease, Parkinson's disease, depression, and diabetes.

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Modeling familial British and Danish dementia

Cited by 46 publications

References 54 publications

Increased AβPP Processing in Familial Danish Dementia Patients

Increased AβPP Processing in Familial Danish Dementia Patients

Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

Staging Neurological Disorders: Expressions of Cognitive and Motor Disorder

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