Mutations

PSEN1 L166P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Genome Build: GRCh37 (105)
Position: Chr14:73653577 T>C
dbSNP ID: rs63750265
Coding/Non-Coding: Coding
Genomic Region: Exon 6
Mutation Type: Point, Missense
Codon Change: CTT to CCT
Research Models: 1

Findings

This appears to be a relatively rare mutation associated with a very early age of symptom onset. It has been identified in a single family. The female proband developed secondary generalized seizures at age 15, major depression at age 19, and memory impairment by age 24. Ataxia and spastic paraparesis were recorded by age 27, and moderate-stage dementia by 28. Dementia, ataxia, and spasticity progressed until death at age 35. Family history details were not reported (Moehlmann et al., 2002).

Neuropathology

Postmortem examination of the proband’s brain revealed numerous Aβ-positive neuritic and cotton-wool plaques throughout the cerebral cortex. Aβ-positive amyloid cores were abundant in the cerebellar cortex (Moehlmann et al., 2002).

Biological Effect

When expressed in different cell lines, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage of APP. This resulted in reduced intracellular and secreted levels of Aβ40 and an increased Aβ42/Aβ40 ratio (Li et al., 2016; Sannerud et al., 2016). The mutation also reduced the endoproteolytic ε-cleavage of N-cadherin and Notch (Moehlmann et al., 2002Sannerud et al., 2016). Additionally, this mutation caused PSEN1 to localize to endolysosomal compartments, similar to the distribution of PSEN2 (Sannerud et al., 2016; see May 2016 news).

 

Research Models

This mutation has been introduced into mouse models including the double transgenic model, APPPS1, which also expresses APP with the Swedish mutation.

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References

Research Models Citations

  1. APPPS1

News Citations

  1. Lodged in Late Endosomes, Presenilin 2 Churns Out Intraneuronal Aβ

Paper Citations

  1. . Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. PubMed.
  2. . Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
  3. . Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell. 2016 Jun 30;166(1):193-208. Epub 2016 Jun 9 PubMed.

Further Reading

Papers

  1. . Genetic mutations associated with presenile dementia. Neurobiology of Aging 23 (1S): S322, 2002
  2. . Convergence of pathology in dementia with Lewy bodies and Alzheimer's disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease. Brain. 2014 Jul;137(Pt 7):1958-70. Epub 2014 May 24 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. PubMed.

Other mutations at this position

Alzpedia