Mutations

APP F690_V695del (Uppsala deletion)

Other Names: Uppsala deletion, APP Δ690-695, APP delta690–695, Uppsala APP deletion

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27264160_27264177 TTCTTTGCAGAAGATGTG>------------------
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: TTC.TTT.GCA.GAA.GAT.GTG to ---.---.---.---.---.---
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This six-amino-acid deletion within the mid-region of Aβ was found to segregate with disease in a Swedish family with a multigeneration history of early onset Alzheimer’s disease. The mutation appears to largely eliminate non-amyloidogenic, α-secretase processing of APP, and leads to the generation of rapidly aggregating Aβ peptides lacking amino acids 19-24.

The “Uppsala deletion” was identified in three affected family members—two siblings and their cousin —from a three-generation pedigree showing an autosomal-dominant pattern of inheritance of disease. Affected family members suffered from severe dementia, with symptom onset in their 40s, and death occurring five to 15 years later. The mutation was absent in older, unaffected family members and more than 500 Swedish healthy controls and patients with sporadic AD.

Biomarkers

Core AD biomarkers in cerebrospinal fluid—Aβ42, total tau, and phospho-tau—were measured in the three index cases: While levels of total tau and phospho-tau were elevated, as seen in sporadic AD, levels of Aβ42 were within the normal range (i.e., the carriers did not exhibit the drop in CSF Aβ42 characteristic of sporadic AD). These relatively high levels of Aβ42 may reflect elevations in Aβ generated from the mutant allele, as discussed below.

Amyloid-PET imaging with Pittsburgh Compound B in two of the mutation carriers revealed only mild elevations of tracer uptake in the cerebral cortex. (Paradoxically, when one of these subjects came to autopsy, abundant amyloid plaques were seen in tissue sections stained with Thioflavin-S or antibodies directed against Aβ.)

CT scans showed medial temporal lobe atrophy in one of the siblings, while the other two carriers exhibited moderate global cortical atrophy with sparing of the temporal lobes.

FDG-PET revealed hypometabolism in the temporal and parietal lobes of all three carriers.

Neuropathology

One carrier of the Uppsala deletion—one of the siblings mentioned above—is deceased, and his or her brain has been examined. Autopsy confirmed AD pathology, with dilated ventricles, abundant amyloid plaques (Thal stage 5) and neurofibrillary tangles (Braak Stage 6),and gliosis in limbic regions and neocortex.

Mass spectrometric analysis showed that plaques were composed primarily of Aβ42 generated from the mutant APP allele and thus lacking amino acids 19-24 (AβUpp42Δ19–24). In addition to full-length AβUpp42Δ19–24, several N-terminally truncated forms were detected, including peptides starting at positions 3 (pyroglutamate), 4, 5, or 8.

Biological Effects

Compared with brains from subjects with sporadic AD, the level of Aβ42 in the brain of the carrier was elevated, while the amount of Aβ40 was decreased.

In vitro studies showed that the mutation largely eliminates non-amyloidogenic processing of APP, with an accompanying increase in amyloidogenic processing: Levels of sAPPα in the culture media of HEK293 cells transfected with mutant APP (APPUpp) were at background levels, in contrast to the elevated levels found in the media of cells transfected with wild-type APP, while more sAPPβ was released by the cells transfected with APPUpp than by cells carrying wild-type APP. Consistent with these findings, levels of CTFα were lower and CTFβ were higher in cells transfected with APPUpp, compared with cells transfected with wild-type APP. Levels of Aβ peptides were also elevated in the media of APPUpp-transfected cells.

The Uppsala deletion also seems to create a new major cleavage site in APP, between amino acids 4 and 5 of the Aβ sequence. In media from cells transfected with wild-type APP, the most prevalent APP metabolites were Aβ1–40 and the p3 peptide generated by sequential α- and γ-secretase cleavages. In cells transfected with APPUpp, the predominant APP metabolites were AβUpp1–40Δ19–24 (Aβ40 missing amino acids 19-24) and an N-terminally truncated peptide, AβUpp5–40Δ19–24. The latter peptide is not merely a cell culture artifact, as AβUpp5–40Δ19–24 was found in the CSF of APP Uppsala mutation carriers.

Cleavage at the β' site in APP (between amino acids 10 and 11 of Aβ) was also increased by the Uppsala deletion: Aβ11–40Δ19–24 and Aβ11– 42Δ19–24 were found in culture media from HEK29 cells transfected with APPUpp and in CSF from mutation carriers. Aβp11– 42Δ19–24 was also detected in plaques from the brain of the deceased carrier.

The propensity of AβUpp1–42Δ19-24 to aggregate was evaluated using synthetic peptides. AβUpp1–42Δ19-24 formed fibrils more quickly than did wild-type Aβ42, at a rate similar to Aβ42 with the Arctic mutation (Aβ42Arc). While the amounts of soluble Aβ oligomers and protofibrils formed by wild-type Aβ42 and Aβ42Arc increased over time, these species decreased for AβUpp1–42Δ19-24, possibly because they represent intermediates that are quickly consumed on the way to fibril formation. Findings from biochemical analyses of the brain of the deceased mutation carrier were consistent with increased generation of insoluble fibrils at the expense of soluble aggregates: Although levels of insoluble Aβ42 were elevated in the mutation carrier, compared with sporadic AD, levels of soluble oligomers and protofibrils were lower.

Electron microscopy of fibrils formed by synthetic AβUpp1–42Δ19-24 showed at least four morphologies. Cryo-EM structural analyses of the two most prominent polymorphs revealed unique structures that differed from previously described Aβ42 fibrils.

Last Updated: 25 Aug 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

  1. APP E693G (Arctic)

Further Reading

Protein Diagram

Primary Papers

  1. . The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation. Sci Transl Med. 2021 Aug 11;13(606) PubMed.

Other mutations at this position

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.