Pagnon de la Vega M, Giedraitis V, Michno W, Kilander L, Güner G, Zielinski M, Löwenmark M, Brundin R, Danfors T, Söderberg L, Alafuzoff I, Nilsson LN, Erlandsson A, Willbold D, Müller SA, Schröder GF, Hanrieder J, Lichtenthaler SF, Lannfelt L, Sehlin D, Ingelsson M. 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. Correction.

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  1. The report by Pagnon de la Vega et al. of a novel APP intra-Aβ deletion brings the opportunity for a deeper understanding of the role of Aβ in pathogenesis of AD. The pattern of PET amyloid tracer retention, in general, and PiB, in particular, has been recognized to be qualitatively and quantitatively different from that in LOAD since our first publication in this area (Klunk et al., 2007).

    Depending on the type of mutation, it can be quite predominant in the striatum (as figure 1E suggests). Cortical surface projections such as those shown in figure 1F do not capture this deposition in the basal ganglia and can thus appear only "slightly positive" as described by the authors. In many ADAD mutation types (and Down's syndrome), this may be explained by a predominance of the "cotton-wool" type of amyloid plaque. 

    However, the Thio-S positivity of the brain examined here suggests otherwise in this case. (By the way, Thio-T and not Thio-S is structurally similar to PiB—although all three, like Congo red, have an affinity for β-sheet fibrils.) One likely issue that may have caused artifactually low apparent PiB retention was the use of the cerebellum as the reference region in this study—as is commonly done in LOAD. It must be assumed that this was the case until proven otherwise by the use of another reference region such as a white-matter area, given that it was stated that, "The regional distribution of Aβ aggregates was extended from neocortex to cerebellum ...", plus the fact that other ADAD mutations have unusually high cerebellar fibrillar amyloid deposition. 

    Pagnon de la Vega et al. discuss this possibility, but dismiss it due to a low Thio-S-measured burden of cerebellar amyloid in sibling-2. However, the best resolution of this possible artifact would be a recalculation using a white-matter reference. It would also be of great interest to examine the binding of [H-3]PiB to purified fibrils of AβUpp1–42D19–24 and compare the Bmax and affinity to that of Aβwt1-42.

    Thus, while the apparently low PiB retention may have a relatively simple methodological explanation, many other interesting findings in this case are more difficult to reconcile with known patterns in LOAD and ADAD. One is the normal (i.e., not reduced) Aβ42 in the CSF. The authors suggest that this is due to overproduction, but could this be due to a normally maintained clearance mechanism in the mutation as well? Other forms of ADAD and Down's syndrome have increased production, but still show decreased CSF Aβ. It did seem like there was relatively little cerebrovascular amyloid in this case and that may also relate to maintenance of normal clearance. 

    Another is the relative lack of oligomeric forms of AβUpp1–42D19–24 along with the fairly typical—even aggressive—clinical course of the dementia. This suggests the pathogenicity of the fibrillar forms of this peptide is high, although the authors seem to dismiss this without much explanation, as well.

    References:

    Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, Dekosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.

    View all comments by William Klunk

  2. This new, interesting mutation offers yet additional compelling evidence in favor of the amyloid cascade hypothesis.

    Interestingly, the Uppsala APP mutation seems to cause AD by both increasing BACE1 cleavage of APP to generate more Aβ, but it also alters the Aβ structure to favor more aggressive Aβ deposition. In a sense, it is like combining the Swedish mutation that makes APP a better substrate for BACE1 together with the Arctic mutation that increases fibrillogenesis—a double whammy that marries increased Aβ production with aggressive aggregation.

    That probably explains the exceptionally early age of AD onset of the Uppsala APP mutation carriers. So although this paper does not really shed new conceptual light on the pathogenic mechanism of familial AD, which we already know involves increased Aβ production, Aβ42/40 ratio, or Aβ aggregation, it does strongly support the well-established concept that amyloid accumulation is a critical early step in AD pathogenesis.

    View all comments by Robert Vassar

  3. This interesting paper on a family from Uppsala shows that an intra-Aβ deletion of six amino acids (residues 19-24) caused dominantly inherited Alzheimer’s disease with abundant plaques and tangles. The deletion altered APP processing and increased the assembly of recombinant Aβ42(Δ19-24) into filaments.

    As expected, Aβ42 was the major component of Aβ pathology in mutation carriers. Despite the finding that recombinant Aβ1-40(Δ19-24) did not assemble into filaments, some Aβ40 deposits were present in brain. At low pH, recombinant Aβ1-42(Δ19-24) assembled into polymorphic filaments.

    Cryo-EM structures of the dominant polymorphs were obtained at 5.7 Å and 5.1 Å resolution. Each polymorph was made of two identical protofilaments, but the low-resolution structures precluded amino acid assignments. It is therefore difficult to compare them with the 4 Å cryo-EM structures of assembled full-length recombinant Aβ(1-42) (Gremer et al., 2017). Residues 19-24 form the beginning of the S-shaped domain that was also observed in the solid-state NMR structures of in vitro aggregated filaments of Aβ42 (Xiao et al., 2015; Colvin et al., 2016; Wälti et al., 2016). 

    It remains to be seen how the high-resolution structures of Aβ42 filaments from human brain compare with those assembled from recombinant proteins.

    References:

    Colvin MT, Silvers R, Ni QZ, Can TV, Sergeyev I, Rosay M, Donovan KJ, Michael B, Wall J, Linse S, Griffin RG. Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils. J Am Chem Soc. 2016 Aug 3;138(30):9663-74. Epub 2016 Jul 14 PubMed.

    Gremer L, Schölzel D, Schenk C, Reinartz E, Labahn J, Ravelli RB, Tusche M, Lopez-Iglesias C, Hoyer W, Heise H, Willbold D, Schröder GF. Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science. 2017 Oct 6;358(6359):116-119. Epub 2017 Sep 7 PubMed.

    Wälti MA, Ravotti F, Arai H, Glabe CG, Wall JS, Böckmann A, Güntert P, Meier BH, Riek R. Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):E4976-84. Epub 2016 Jul 28 PubMed.

    Xiao Y, Ma B, McElheny D, Parthasarathy S, Long F, Hoshi M, Nussinov R, Ishii Y. Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nat Struct Mol Biol. 2015 Jun;22(6):499-505. Epub 2015 May 4 PubMed.

    View all comments by Michel Goedert

  4. This Uppsala deletion is entirely consistent with the general theory that Aβ accumulation causes AD, and that Aβ drives tau aggregation.

    As we enter the era of disease-modifying therapies, the pathogenic mechanisms revealed in this study reinforce the need to develop combination strategies that tackle both Aβ clearance and production, either at the same time or sequentially. Passive immunotherapies followed by low-dose BACE1 inhibitors should work in pedigrees such as in this unfortunate family. The tools are available right now. It’s time we applied them.

    View all comments by Colin Masters

  5. I find this paper quite intriguing, in terms of potentially three mechanisms for the Uppsala mutation's increased Aβ42 accumulation and subsequent downstream AD pathology and clinical features.

    The authors did a very nice job teasing out much of the mechanism of this unusual deletion mutation. I am not sure it has direct implications for conventional cases of APP processing and AD development, but it is certainly an interesting and unfortunate error of nature. It does provide another biochemical pathway by which lifelong altered Aβ production and aggregation can produce progressive tauopathy and clinical Alzheimer’s disease.

    View all comments by Dennis Selkoe

  6. We would like to highlight a major contradiction between the data and the conclusions in this paper. A key finding is noted as follows: “The amounts of Aβwt1–40 in CSF, produced from their nonmutated APP allele, were lower in patients with the Uppsala APP mutation than in sAD cases and control subjects, whereas Aβwt1–42 was not different in patients with the mutations compared to controls (Fig. 4C)”. However, the data presented in figure 4 clearly shows that the CSF levels of the wild-type (wt), 42 amino acid Aβ42 are significantly lower in mutation carriers compared to controls. As a result, the statement in the Abstract, that “Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aβ42 and only slightly pathological amyloid–positron emission tomography signals,” is incorrect and must be amended. The proper interpretation of the data is critical since this is a new and important mutation that could help understand the pathogenic mechanisms of Alzheimer’s disease.

    This clarification is also essential for the discussion on whether Aβ42-related mutations cause Alzheimer's disease via an increase in the soluble Aβ42 to toxic levels, or due to depletion of Aβ42, leading to haploinsufficiency-type loss-of-function. We have recently demonstrated that in amyloid PET-positive individuals, higher levels of soluble Aβ42 in the CSF are associated with normal cognition whereas lower levels are associated with dementia, irrespective of the amyloid plaque load (Sturchio et al., 2021). This is also the case in this report, where mutation carriers with low levels of CSF soluble Aβ42 and nearly normal PET are symptomatic. The data, therefore, support a toxic mechanism for cognitive impairment to be due to Aβ42 depletion rather than its aggregation into plaques (Espay et al, 2021).

    References:

    Sturchio A, Dwivedi AK, Young CB, Malm T, Marsili L, Sharma JS, Mahajan A, Hill EJ, Andaloussi SE, Poston KL, Manfredsson FP, Schneider LS, Ezzat K, Espay AJ. High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis. EClinicalMedicine, 0, 100988. 2021

    Espay AJ, Sturchio A, Schneider LS, Ezzat K. Soluble Amyloid-β Consumption in Alzheimer's Disease. J Alzheimers Dis. 2021;82(4):1403-1415. PubMed.

    View all comments by Alberto Espay

  7. We appreciate the insightful comment by Drs. Ezzat and Espay and are grateful that our colleagues noticed an incorrect statement with respect to the MS-based levels of Aβwt1-42, which were indeed lower in mutation carriers as compared to control subjects. We will seek to have this error corrected in the online version of the paper and/or pointed out as an erratum in the next issue of the journal.

    However, we still believe that it is correct to state that mutation carriers had normal CSF levels of Aβ1-42 as we here refer to the ELISA-based AD biomarker. Based on that method, the levels were indeed in the normal range (table S1). However, as the diagnostic ELISA presumably cannot discriminate between the wild-type and the mutated Aβ species (and thus should measure total Aβ1-42), we performed IP-MS which demonstrated that whereas levels of Aβwt1-42 were indeed lower in mutation carriers than in controls, and were similar to those in sporadic AD cases, (fig. 4c), the relative levels of AβUpp1-42Δ19-24 were substantially higher (fig. 4d). When combining these two measurements (to generate total Aβ1-42), the levels were again increased, as opposed to the expected decrease seen for sporadic AD CSF (fig. 4b). Thus, we believe that the more detailed IP-MS analyses offer an explanation as to why the ELISA-based levels of the biomarker Aβ1-42 were not pathologically lowered but were instead in the normal range.

    In addition, analyses of post mortem brain tissue from the Uppsala APP mutation carrier revealed high levels of Aβ1-42 both in the TBS and formic acid soluble fractions (figs. 3a-b), suggesting a combination of increased production and deposition in the brain of Aβ1-42. Based on these findings, and on the fact that the mutants were found to display an increased fibrillization rate, we would argue that our data mainly speak in favor of a toxic gain of function for at least this particular APP mutation.

    View all comments by Dag Sehlin

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Mutations

  1. APP F690_V695del (Uppsala deletion)

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  1. Double Whammy: APP Uppsala Deletion Ups Aβ and Its Aggregation Propensity