Wyniki wyszukiwania

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Genetic study of familial cases of Alzheimer's disease

100%

Kowalska A., Pruchnik-Wolinska D., Florczak J., Modestowicz R., Szczech J., Kozubski W., Rossa G., Wender M.

Acta Biochimica Polonica

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2004

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tom 51

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nr 1

A small number (1-5%) of Alzheimer's disease (AD) cases associated with the early-onset form of the disease (EOAD) appears to be transmitted as a pure genetic, autosomal dominant trait. To date, three genes responsible for familial EOAD have been identified in the human genome: amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). Mutations in these genes account for a significant fraction (18 to 50%) of familial cases of early onset AD. The mutations affect APP processing causing increased production of the toxic Aβ42 peptide. According to the "amyloid cascade hypothesis", aggregation of the Aβ42 peptide in brain is a primary event in AD pathogenesis. In our study of twenty AD patients with a positive family history of dementia, 15% (3 of 20) of the cases could be explained by coding sequence mutations in the PS1 gene. Although a frequency of PS1 mutations is less than 2% in the whole population of AD patients, their detection has a significant diagnostic value for both genetic counseling and treatment in families with AD.

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Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznan Region

80%

Kowalska A., Wender M., Florczak J., Pruchnik-Wolinska D., Modestowicz R., Szczech J., Rossa G., Kozubski W.

Journal of Applied Genetics

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2003

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tom 44

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nr 2

3

Molecular mechanisms initiating amyloid beta-fibril formation in Alzheimer's disease

80%

Kirkitadze M. D., Kowalska A.

Acta Biochimica Polonica

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2005

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tom 52

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nr 2

The deposition of aggregated amyloid β-protein (Aβ) in the human brain is a major lesion in Alzheimer’s disease (AD). The process of Aβ fibril formation is associated with a cascade of neuropathogenic events that induces brain neurodegeneration leading to the cognitive and behavioral decline characteristic of AD. Although a detailed knowledge of Aβ assembly is crucial for the development of new therapeutic approaches, our understanding of the molecular mechanisms underlying the initiation of Aβ fibril formation remains very incomplete. The genetic defects responsible for familial AD influence fibrillogenesis. In a majority of familial cases determined by amyloid precursor protein (APP) and presenilin (PS) mutations, a significant overproduction of Aβ and an increase in the Aβ42/Aβ40 ratio are observed. Recently, it was shown that the two main alloforms of Aβ have distinct biological activity and behaviour at the earliest stage of assembly. In vitro studies demonstrated that Aβ42 monomers, but not Aβ40, form initial and minimal structures (pentamer/hexamer units called paranuclei) that can oligomerize to larger forms. It is now apparent that Aβ oligomers and protofibrils are more neurotoxic than mature Aβ fibrils or amyloid plaques. The neurotoxicity of the prefibrillar aggregates appears to result from their ability to impair fundamental cellular processes by interacting with the cellular membrane, causing oxidative stress and increasing free Ca2+ that eventually lead to apoptotic cell death.

Ograniczanie wyników

2 Acta Biochimica Polonica

1 Journal of Applied Genetics

3 Kowalska A.

2 Florczak J.

2 Kozubski W.

2 Modestowicz R.

2 Pruchnik-Wolinska D.

2 Rossa G.

2 Szczech J.

2 Wender M.

1 Kirkitadze M. D.

1 2005

1 2004

1 2003

Genetic study of familial cases of Alzheimer's disease

Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznan Region

Molecular mechanisms initiating amyloid beta-fibril formation in Alzheimer's disease