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.

History

The

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

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 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. The mutation had important consequences for Alzheimer's disease research. The mutation occurs in the gene which encodes

amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...

(APP), which is proteolysed into

beta amyloid Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor pro ...

. Beta amyloid is one of the

peptides Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Dalton (unit), Da or more are called proteins. Chains of fewer t ...

which accumulate in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

s of people with Alzheimer's disease. A great debate had existed between Alzheimer's disease researchers about the relevance of

amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...

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 Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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 A genetically modified mouse, genetically engineered mouse model (GEMM) or transgenic mouse is a mouse (''Mus musculus'') that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly use ...

model of Alzheimer's disease. Transgenic mice (e.g. Tg2576) were made which overproduce human APP with the Swedish mutation. As a consequence, the mice can develop amyloid plaques at around 13 months old. It is thought that the Swedish mutation causes early-onset Alzheimer's disease by

beta-secretase Beta-secretase is a protein family that includes in humans Beta-secretase 1 and Beta-secretase 2. References {{enzyme index Single-pass transmembrane proteins ...

cleavage within the secretory pathway. The Swedish mutation mice are used to study the effects of amyloid plaques and to develop potential treatments for Alzheimer's disease.

References

{{Reflist, 33em Medical genetics Genetic diseases and disorders Rare diseases Alzheimer's disease

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

History

See also

References