| 1. |
- de la Vega, Maria Pagnon, et al.
(författare)
-
The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation
- 2021
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:606
-
Tidskriftsartikel (refereegranskat)abstract
- Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.
|
|
| 2. |
- Pagnon de la Vega, María, et al.
(författare)
-
Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
- 2024
-
Ingår i: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.
|
|
| 3. |
- Pagnon de la Vega, María, 1994-
(författare)
-
Characterization of the novel “Uppsala mutation” causing a familial form of early onset Alzheimer’s disease
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Alzheimer’s disease (AD) brain displays extracellular plaques of amyloid-β (Aβ), neurofibrillary tangles of tau and neuronal loss. The 40-42 amino acid Aβ peptide is formed from the amyloid precursor protein (APP) by β-secretase and γ-secretase, while α-secretase prevents Aβ generation. According to the amyloid cascade hypothesis, AD is initiated by increased brain levels of toxic Aβ species. Our laboratory has previously identified two APP mutations, causing early onset AD. Whereas the Swedish mutation results in increased β-secretase cleavage leading to higher Aβ levels, the Arctic mutation leads to a conformational Aβ change that promotes formation of toxic Aβ protofibrils.In this thesis, we have performed a screen for novel disease-causing mutations in 102 patients with early onset dementia disorders, who underwent investigation at the Memory clinic at Uppsala University Hospital. Mainly, we found a new APP mutation, which causes familial dominantly inherited AD with age at symptom onset in the early forties. This Uppsala APP mutation, consists of an intra-Aβ deletion of six consecutive amino acids, which results in Aβ with 34-36 amino acids (AβUppΔ19-24).Affected mutation-carriers develop symptoms typical of AD. As for biomarkers, the patients display expected changes although brain Aβ imaging by [11C]PIB-PET is only slightly pathological and Aβ42-analysis of cerebrospinal fluid yields normal results. By investigating neuropathological, biochemical and structural properties of AβUppΔ19-24 in patient samples, on synthetic peptides and in cell culture models we found evidence that Uppsala APP is pathogenic via three mechanisms: increased β-secretase cleavage, altered α-secretase cleavage and rapid formation of Aβ fibrils into unique polymorphs.To allow for in vivo studies of molecular mechanisms related to the Uppsala APP mutation we generated transgenic mice, expressing human APP with this mutation together with Swedish APP (to increase Aβ levels). In the brain of tg-UppSwe mice, we observed diffuse aggregates of mainly AβUpp42Δ19-24, which, given their normal γ-secretase activity, distinguishes these mice from most transgenic mouse models. In order to study if AβUppΔ19-24 co-aggregates with wild-type Aβ (Aβwt), we crossed tg-UppSwe with tg-Swe. Analyses of brains from such mice indicated that AβUppΔ19-24 may act as seeds for Aβwt by changing its aggregation behavior and thereby increasing its deposition in brain.Taken together, our studies of the Uppsala APP mutation have provided new knowledge of pathogenic molecular mechanisms in AD and of basic Aβ biology. Such insights may in a longer perspective help us to develop new diagnostics and therapeutics for this disorder.
|
|
| 4. |
- Pagnon de la Vega, María, 1994-, et al.
(författare)
-
Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer’s disease and frontotemporal dementia
- 2022
-
Ingår i: BMC Genomics. - : Springer Nature. - 1471-2164. ; 23
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Most dementia disorders have a clear genetic background and a number of disease genes have beenidentified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genesfor the amyloid-β precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inheritedforms of Alzheimer’s disease (AD).Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects ofsuch mutations have proven important for understanding the pathogenic processes. Here, we performed a screen toidentify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation.Results: Using targeted exome sequencing we have screened all coding exons in eleven known dementia genes(PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, otherdementia diagnoses or mild cognitive impairment.We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met-146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation,named the Uppsala mutation, consists of a six amino acid intra-amyloid β deletion.In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE ε4was prevalent in this patient group with an allele frequency of 54%Conclusions: Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP,as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart fromgiving important information to the clinical investigation, the identification of disease mutations can contribute to anincreased understanding of disease mechanisms.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
