Swedish mutation: Difference between revisions

Latest revision as of 02:27, 3 April 2025

Swedish mutation refers to a rare genetic mutation in the amyloid precursor protein (APP) gene that causes early-onset familial Alzheimer's disease (EOFAD). This mutation is one of the most well-known and widely studied genetic variations associated with Alzheimer's disease, and it has played a significant role in shaping modern Alzheimer's disease research and therapeutic strategies.

History[edit]

The Swedish mutation was identified in 1992 by Dr. Michael Mullan and Dr. Fiona Crawford at the University of South Florida, using DNA samples provided by a team of Swedish researchers led by Dr. Lars Lannfelt. The mutation was discovered in two related Swedish families with a history of early-onset dementia.

This specific mutation leads to the development of Alzheimer's disease symptoms in affected individuals during their early 50s. As an autosomal dominant condition, each child of an affected individual has a 50% chance of inheriting the mutation. Despite its importance, the mutation is extremely rare and has only been documented in these two Swedish families; it has not been found in the general population elsewhere.

Genetics[edit]

The mutation involves a double missense mutation (KM670/671NL) in the gene encoding amyloid precursor protein (APP). This gene, located on chromosome 21, encodes a transmembrane protein that is cleaved by enzymes to produce beta-amyloid peptides.

In individuals with the Swedish mutation, abnormal processing of APP by the enzyme beta-secretase occurs within the secretory pathway, resulting in increased production of the neurotoxic peptide amyloid beta (Aβ), especially the Aβ40 and Aβ42 isoforms. These peptides aggregate and form amyloid plaques—a hallmark of Alzheimer's pathology.

Significance in Research[edit]

Before the discovery of the Swedish mutation, the role of amyloid plaques in Alzheimer's disease was widely debated. Some researchers believed that amyloid deposition was a secondary or terminal event ("tombstone") rather than a causative factor.

However, the finding that this single mutation in the APP gene was both necessary and sufficient to cause Alzheimer's disease in these families provided compelling evidence supporting the amyloid hypothesis—the theory that accumulation of amyloid beta is a primary event in the disease process.

The discovery contributed to:

Validating APP and amyloid beta as targets for drug development.
Supporting the use of transgenic animal models for studying Alzheimer's disease.
Accelerating efforts to develop disease-modifying treatments aimed at reducing amyloid burden in the brain.

Transgenic Models[edit]

The mutation was introduced into mice to develop transgenic models of Alzheimer's disease, such as the Tg2576 mouse. These mice express human APP with the Swedish mutation and begin to develop amyloid plaques at around 13 months of age, mimicking key features of the human disease.

These models are widely used to:

Investigate the role of amyloid pathology in neurodegeneration.
Study cognitive decline and memory loss.
Evaluate potential Alzheimer's disease treatments including immunotherapy, beta-secretase inhibitors, and gamma-secretase inhibitors.

Pathophysiology[edit]

The mutation leads to enhanced cleavage of APP by beta-secretase, bypassing the normal alpha-secretase pathway. This results in an overproduction of amyloid beta peptides, particularly Aβ42, which is more prone to aggregation and is neurotoxic. Amyloid plaques interfere with synaptic function, promote inflammation, and contribute to neuronal cell death.

Inheritance[edit]

The Swedish mutation follows an autosomal dominant inheritance pattern. Affected individuals usually present with symptoms of Alzheimer's disease between ages 50 and 60, including:

Progressive memory loss
Cognitive decline
Personality changes
Loss of executive function

Impact on Therapeutics[edit]

Because of the Swedish mutation's direct role in increasing amyloid beta production, it has become a key target in developing:

Monoclonal antibodies against amyloid (e.g., aducanumab)
Small molecule inhibitors of beta-secretase (BACE)
APP-processing modulators

External links[edit]

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-The '''Swedish mutation''', or '''familial Alzheimer's disease genetic mutation''', is one of the most well known genetic variations that causes [[early-onset familial Alzheimer's disease]].<ref>{{cite journal | vauthors = Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L | title = A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid | journal = Nature Genetics | volume = 1 | issue = 5 | pages = 345–7 | date = August 1992 | pmid = 1302033 | doi = 10.1038/ng0892-345 }}</ref>
+{{DISPLAYTITLE:Swedish mutation}}
+'''Swedish mutation''' refers to a rare genetic mutation in the [[amyloid precursor protein]] (''APP'') gene that causes [[early-onset familial Alzheimer's disease]] (EOFAD). This mutation is one of the most well-known and widely studied genetic variations associated with Alzheimer's disease, and it has played a significant role in shaping modern [[Alzheimer's disease]] research and therapeutic strategies.
 ==History==
-The [[mutation]] was found in 1992 in Florida by Dr. [[Michael Mullan]] and Dr. Fiona Crawford working on DNA samples supplied by a group of Swedish researchers led by Dr [[Lars Lannfelt]].
+The Swedish mutation was identified in 1992 by Dr. Michael Mullan and Dr. Fiona Crawford at the University of South Florida, using DNA samples provided by a team of Swedish researchers led by Dr. Lars Lannfelt. The mutation was discovered in two related Swedish families with a history of early-onset [[dementia]].
-The genetic error causes Alzheimer's disease to develop in the early 50s for the family members who inherit it. On average, about half of the children of someone who carries the mutation will inherit it. The mutation is extremely rare – it has only ever been found in two Swedish families and has never been found in the general population in any other countries.
+This specific mutation leads to the development of Alzheimer's disease symptoms in affected individuals during their early 50s. As an [[autosomal dominant]] condition, each child of an affected individual has a 50% chance of inheriting the mutation. Despite its importance, the mutation is extremely rare and has only been documented in these two Swedish families; it has not been found in the general population elsewhere.
-The mutation had important consequences for Alzheimer's disease research. The mutation occurs in the gene which encodes [[amyloid precursor protein]] (APP), which is [[Proteolysis|proteolysed]] into [[beta amyloid]].<ref>{{cite journal | vauthors = Wilson CA, Doms RW, Lee VM | title = Intracellular APP processing and A beta production in Alzheimer disease | journal = Journal of Neuropathology and Experimental Neurology | volume = 58 | issue = 8 | pages = 787–94 | date = August 1999 | pmid = 10446803 | doi = 10.1097/00005072-199908000-00001 }}</ref> Beta amyloid is one of the [[peptides]] which accumulate in the [[brain]]s of people with Alzheimer's disease. A great debate had existed between Alzheimer's disease researchers about the relevance of [[amyloid]] prior to the 1990s – many scientists believed amyloid was a tombstone of the disease and was not critical to the development of the disease. However, because the only difference between the family members who developed Alzheimer's disease and those that did not in these families was the inheritance of the mutation in the amyloid gene, this suggested that the amyloid [[protein]] itself could cause the disease. The idea that amyloid could cause the disease influenced scientific research until this day. Many experimental treatments are directed towards lowering amyloid levels in the brain. The other main effect the discovery of the Swedish mutation had was to provide one [[transgenic mouse]] model of Alzheimer's disease. Transgenic mice (e.g. Tg2576)<ref name=Tg2576>{{cite web|title=Tg2576|url=http://www.criver.com/products-services/drug-discovery/capabilities-platforms/in-vivo-pharmacology/central-nervous-system-pain/alzheimer-s-disease-model/tg2576|access-date=2016-12-31|archive-url=https://web.archive.org/web/20170101003857/http://www.criver.com/products-services/drug-discovery/capabilities-platforms/in-vivo-pharmacology/central-nervous-system-pain/alzheimer-s-disease-model/tg2576|archive-date=2017-01-01|dead-url=yes|df=}}</ref> were made which overproduce human APP with the Swedish mutation. As a consequence, the mice can develop amyloid plaques at around 13 months old.<ref name=Tg2576/>
+==Genetics==
+The mutation involves a double missense mutation (KM670/671NL) in the gene encoding [[amyloid precursor protein]] (APP). This gene, located on [[chromosome 21]], encodes a transmembrane protein that is cleaved by enzymes to produce [[beta-amyloid]] peptides.
-It is thought that the Swedish mutation causes early-onset Alzheimer's disease by [[beta-secretase]] cleavage within the secretory pathway.<ref>{{cite journal | vauthors = Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, Lannfelt L, Selkoe DJ | title = The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway | journal = Nature Medicine | volume = 1 | issue = 12 | pages = 1291–6 | date = December 1995 | pmid = 7489411 | doi = 10.1038/nm1295-1291 }}</ref>
+In individuals with the Swedish mutation, abnormal processing of APP by the enzyme [[beta-secretase]] occurs within the [[secretory pathway]], resulting in increased production of the neurotoxic peptide [[amyloid beta (Aβ)]], especially the Aβ40 and Aβ42 isoforms. These peptides aggregate and form [[amyloid plaques]]—a hallmark of Alzheimer's pathology.
-The Swedish mutation mice are used to study the effects of amyloid plaques and to develop potential treatments for Alzheimer's disease.<ref>{{cite journal | vauthors = Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ | title = Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models | journal = Frontiers in Genetics | volume = 5 | pages = 88 | year = 2014 | pmid = 24795750 | pmc = 4005958 | doi = 10.3389/fgene.2014.00088 }}</ref>
+==Significance in Research==
+Before the discovery of the Swedish mutation, the role of amyloid plaques in Alzheimer's disease was widely debated. Some researchers believed that amyloid deposition was a secondary or terminal event ("tombstone") rather than a causative factor.
-== See also ==
+However, the finding that this single mutation in the APP gene was both necessary and sufficient to cause Alzheimer's disease in these families provided compelling evidence supporting the [[amyloid hypothesis]]—the theory that accumulation of amyloid beta is a primary event in the disease process.
-*[[Early-onset Alzheimer's disease]]
-== References ==
+The discovery contributed to:
-{{Reflist|33em}}
+* Validating APP and amyloid beta as targets for drug development.
+* Supporting the use of transgenic animal models for studying Alzheimer's disease.
+* Accelerating efforts to develop [[disease-modifying treatments]] aimed at reducing amyloid burden in the brain.
-[[Category:Medical genetics]]
+==Transgenic Models==
-[[Category:Genetic diseases and disorders]]
+The mutation was introduced into mice to develop transgenic models of Alzheimer's disease, such as the '''Tg2576 mouse'''. These mice express human APP with the Swedish mutation and begin to develop amyloid plaques at around 13 months of age, mimicking key features of the human disease.
+These models are widely used to:
+* Investigate the role of amyloid pathology in [[neurodegeneration]].
+* Study cognitive decline and [[memory loss]].
+* Evaluate potential [[Alzheimer's disease treatments]] including [[immunotherapy]], [[beta-secretase inhibitors]], and [[gamma-secretase inhibitors]].
+==Pathophysiology==
+The mutation leads to enhanced cleavage of APP by beta-secretase, bypassing the normal [[alpha-secretase]] pathway. This results in an overproduction of amyloid beta peptides, particularly Aβ42, which is more prone to aggregation and is neurotoxic. Amyloid plaques interfere with [[synaptic function]], promote inflammation, and contribute to [[neuronal cell death]].
+==Inheritance==
+The Swedish mutation follows an autosomal dominant inheritance pattern. Affected individuals usually present with symptoms of Alzheimer's disease between ages 50 and 60, including:
+* Progressive [[memory loss]]
+* Cognitive decline
+* Personality changes
+* Loss of executive function
+==Impact on Therapeutics==
+Because of the Swedish mutation's direct role in increasing amyloid beta production, it has become a key target in developing:
+* [[Monoclonal antibodies]] against amyloid (e.g., [[aducanumab]])
+* Small molecule inhibitors of [[beta-secretase (BACE)]]
+* APP-processing modulators
+==See also==
+* [[Amyloid hypothesis]]
+* [[Early-onset Alzheimer's disease]]
+* [[Familial Alzheimer's disease]]
+* [[Alzheimer's disease]]
+* [[Tg2576 mouse]]
+* [[Beta-amyloid]]
+==External links==
+* [https://www.alz.org/ Alzheimer's Association]
+* [https://www.ncbi.nlm.nih.gov/omim/104760 OMIM entry on APP gene]
+{{dementia}}
+[[Category:Alzheimer's disease]]
+[[Category:Genetic disorders]]
+[[Category:Neurodegenerative disorders]]
+[[Category:Mutations]]
+[[Category:Autosomal dominant disorders]]
 [[Category:Rare diseases]]
-[[Category:Alzheimer's disease]]
+{{disease-stub}}
-[[Category:Health in Sweden|Mutation]]
-[[Category:Mental health in Sweden|Mutation]]
-[[Category:Science and technology in Sweden|Mutation]]
-{{dictionary-stub1}}