Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP

In the paper

“Matrix metalloproteinases (MMPs), including MMP-2, MMP-3, MMP-7 and MMP-9 also cleave within the Aβ sequence (Rivera et al., 2019) and these cleavages have been compared to those of membrane-type MMPs (MT-MMPs) in Figure 1.”

What the sources say

• Partly supported

  The Introduction reports that MMP-9 cleaves Aβ at identified sites, that MMP-2 has a similar Aβ-degrading profile, and that MMP-7 cleaves Aβ40 and Aβ42. For MMP-3, it reports Aβ degradation through a mechanism involving MMP-3 activation, but does not establish that MMP-3 itself cleaves within the Aβ sequence. No page numbers are available in our copy. (LLM, conf=0.86)

  cites Rivera et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“The γ-secretase complex is formed by a PS1 or PS2 catalytic subunit and 3 partner proteins, Aph-1, pen-2 and nicastrin (Haass et al., 2012; Rajendran and Annaert, 2012; Masters et al., 2015; Selkoe and Hardy, 2016).”

What the sources say

• Supported

  The γ-Secretase section states that the complex has four subunits: PS1 or PS2, which contains catalytic residues, plus nicastrin, APH-1, and PEN-2. This matches the cited claim. (LLM, conf=0.95)

  cites Haass et al., 2012 source
• ?Not checked — no full text of the sourcecites Rajendran and Annaert, 2012 source
• ?Not checked — no full text of the sourcecites Masters et al., 2015 source

In the paper

“BACE-1 cleaves numerous substrates, which confers this enzyme a wide spectrum of physiological and pathological activities (Kuhn et al., 2012; Zhou et al., 2012; Vassar et al., 2014), but it is indisputably its ability to process APP that has attracted much attention, especially in relation to AD.”

What the sources say

• Partly supported

  The Identification of neuronal BACE1 sheddome section reports 34 neuronal membrane proteins whose shedding depends on BACE1. The Introduction links APP cleavage to pathogenic amyloid production and neuregulin-1 cleavage to myelination. But the Discussion says the functional consequences of cleavage remain unknown for most substrates, so the claim that cleavage confers a wide spectrum of physiological and pathological activities is stronger than the paper establishes. (LLM, conf=0.82)

  cites Kuhn et al., 2012 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Zhou et al., 2012 source
• Supported

  The ‘Additional BACE1 substrates in the CNS’ section says BACE1 has a broad range of substrates within and outside the nervous system. The ‘BACE protease substrates – overview’ section links its substrates to physiological functions, while ‘β-amyloid and Alzheimer’s disease’ describes the pathological consequence of APP processing. No page numbers are available in our copy. (LLM, conf=0.92)

  cites Vassar et al., 2014 source

In the paper

“a few studies indicate that Aβ has antimicrobial activities”

What the sources say

• Supported

  The Results report that synthetic Aβ peptides inhibited the growth of bacteria and yeast in vitro, with activity against seven tested pathogens equivalent to or greater than LL-37. This directly supports the attributed claim that Aβ has antimicrobial activities. (LLM, conf=0.94)

  cites Soscia et al., 2010 source
• ?Not checked — no full text of the sourcecites Moir et al., 2018 source
• Supported

  The Introduction describes Aβ as an antimicrobial peptide. In the section “Aβ1–42 has antibacterial effects against P. gingivalis,” the authors also report that Aβ1–42 significantly increased the proportion of dead or dying bacteria compared with controls. These passages support the attributed statement. (LLM, conf=0.94)

  cites Dominy et al., 2019 source

In the paper

“this inhibitor not only reduces α-cleavage of APP but also the cell surface levels of ADAM10 and APP, which leads to increased endocytosis and β-secretase cleavage”

What the sources say

• Partly supported

  The Discussion reports reduced APP α-cleavage, reduced surface ADAM-10 and APP, increased APP endocytosis, and increased β-cleavage. But the cleavage and surface-level experiments described in the Results used COS7 cells, not neuroblastoma cells; the paper mentions neuroblastoma cells in connection with a gene screen. It also describes enhanced β-cleavage in endosomes as a proposed mechanism, rather than establishing every step of the causal chain. (LLM, conf=0.88)

  cites Hoe et al., 2007 sourceExperimental — accuracy not yet measured

In the paper

“probably reflecting a combination of events triggered by its accumulation, including stimulation of Tau hyperphosphorylation and subsequent formation of neurofibrillary tangles (NFTs), promotion of inflammation and also synaptic dysfunctions”

What the sources say

• ?Not checked — no full text of the sourcecites Benilova et al., 2012 source
• Partly supported

  The paper’s discussion of elevated Aβ and synaptic transmission reports synaptic impairment and loss. Its introductory section also says nonneuronal changes, including microgliosis and astrocytosis, may contribute to neuronal dysfunction. The paper does not establish the claimed sequence from Aβ-induced tau hyperphosphorylation to neurofibrillary tangle formation; tau hyperphosphorylation appears in the title of a work listed in its References, but that does not support the full sequence. (LLM, conf=0.86)

  cites Mucke and Selkoe, 2012 sourceExperimental — accuracy not yet measured
• Supported

  The sections on Aβ-driven tau alteration and synaptic loss report tau hyperphosphorylation, subsequent tau deposition and impaired synaptic function. The Introduction’s Figure 1 description says Aβ oligomers may activate microglia and astrocytes, supporting the claim’s hedged reference to inflammation. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites Selkoe and Hardy, 2016 source

In the paper

“sAPPα interacts with BACE-1 and inhibits Aβ production”

What the sources say

• Supported

  The Results section, “sAPP-α interacts and inhibits BACE1,” reports coprecipitation of sAPP-α with BACE1. The Discussion reports that exogenous sAPP-α inhibited Aβ40 and Aβ42 production in the studied cells. Together, these passages support both parts of the claim. (LLM, conf=0.94)

  cites Obregon et al., 2012 source

In the paper

“and as a Tau- or APP-cleaving enzyme (Zhang et al., 2014, 2015).”

What the sources say

• Supported

  The Introduction identifies asparagine endopeptidase (AEP) as legumain and states that AEP cleaves tau. The Results section, “AEP directly cleaves tau,” reports direct cleavage by purified AEP. This supports the tau-cleaving part of the cited description; the sentence also cites a separate 2015 paper for the alternative APP-cleaving description. (LLM, conf=0.94)

  cites Zhang et al., 2014 source
• Supported

  The Abstract identifies AEP as legumain and states that AEP cleaves tau. The Results section, “APP is a physiological substrate of AEP,” reports direct cleavage of APP by AEP. No page numbers are provided in our copy. (LLM, conf=0.94)

  cites Zhang et al., 2015 source

In the paper

“picomolar concentrations of Aβ are sufficient to stimulate nicotinic receptors and subsequently LTP and learning and memory in healthy rodents (Puzzo et al., 2008, 2012; Morley et al., 2010)”

What the sources say

• Supported

  The Results report that 200 pM Aβ42 enhanced hippocampal LTP and that the enhancement was absent in mice lacking α7 nicotinic receptors. The paper also reports enhanced reference and contextual fear memory and describes a model in which α7 receptor activation mediates these effects. The Discussion leaves open whether Aβ42 interacts directly with the receptors, but the claim does not require direct binding. (LLM, conf=0.86)

  cites Puzzo et al., 2008 source
• ?Not checked — no full text of the sourcecites Puzzo et al., 2012 source
• ?Not checked — no full text of the sourcecites Morley et al., 2010 source

In the paper

“also Tau could cause APP-dependent impairment of LTP and spatial learning in mice (Puzzo et al., 2017).”

What the sources say

• Supported

  In the Results sections on oTau and memory and on oTau and LTP, extracellular Tau oligomers impaired radial-arm water-maze performance and reduced LTP in wild-type mice, but not in APP-knockout mice. This supports the claim that Tau can cause APP-dependent impairment of spatial learning and LTP under the tested conditions. (LLM, conf=0.93)

  cites Puzzo et al., 2017 source

In the paper

“Aβ oligomers and also Tau could cause APP-dependent impairment of LTP and spatial learning in mice (Puzzo et al., 2017)”

What the sources say

• Supported

  The Results sections on oAβ and oTau memory report impaired spatial-learning performance in wild-type mice but not APP-KO mice (Figures 3D and 4D; page numbers unavailable). The Results section on LTP likewise reports impairment from each oligomer in wild-type hippocampal slices but not APP-KO slices (Figure 5B–C). (LLM, conf=0.94)

  cites Puzzo et al., 2017 source

In the paper

“legumain can cleave APP at positions 373 and 585 (APP695 numbering), generating 2 fragments with distinctive cytotoxicity (Zhang et al., 2015).”

What the sources say

• Supported

  The Results section ('AEP cleaves APP at N373 and N585 residues') identifies both cleavage sites using APP695 numbering. In 'APP N-terminal ectodomain shed by AEP cleavage is neurotoxic,' the paper reports that APP1–373 was neurotoxic to primary neurons, whereas APP1–585 showed no demonstrable neurotoxic effect. (LLM, conf=0.92)

  cites Zhang et al., 2015 source

In the paper

“In addition, it was shown that cultured hippocampal neurons with truncated APP gene accumulate APP on the plasma membrane and present reduced colocalization of BACE-1 and APP in endosomes, confirming a key role of the YENPTY sequence in APP internalization and Aβ production by endosomes (Sun et al., 2019).”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Sun et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“bigenic 5xFAD/legumain–/– and 5xFAD/MT5–/– mice both show significant reductions in Aβ burden and glial reactivity, as well as prevention of LTP and learning and memory deficits (Zhang et al., 2015; Baranger et al., 2016b, 2017a)”

What the sources say

• Partly supported

  The Results sections on AEP knockout report reduced Aβ burden, rescued LTP deficits, and protection from spatial-memory impairment in 5XFAD/AEP−/− mice (Figs. 7c–j). Our copy does not report reduced glial reactivity in those mice. The Methods list 5XFAD/AEP−/− mice but not 5XFAD/MT5−/− mice; the latter part of the sentence may be covered by the other citations, but it is not supported by Zhang et al. (LLM, conf=0.88)

  cites Zhang et al., 2015 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Baranger et al., 2016b, 2017a

In the paper

“Endosomes are thought to be the main locus of Aβ production, which is ensured by canonical β- and γ-secretases (Vassar et al., 1999).”

What the sources say

• Not checked yetcites Vassar et al., 1999 source

In the paper

“This type I transmembrane protein of the aspartyl proteinase family needs an acidic environment (optimum pH 4.5) to be enzymatically active (Saric et al., 2013).”

What the sources say

• ?Not checked — no full text of the sourcecites Saric et al., 2013 source

In the paper

“which appears to be a new biomarker of Aβ clearance in AD as it is noticeably increased in mild cognitive impaired patients along with strong BACE-1 activity (Liebsch et al., 2019).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Liebsch et al., 2019 source

In the paper

“Physiologically relevant Aβ degradation has been mainly attributed to 4 metalloproteinases: neprilysin, insulin degrading enzyme, endothelin converting enzyme and angiotensin converting enzyme, the regulation and functions of which have been extensively reviewed elsewhere (De Strooper, 2010; Nalivaeva et al., 2012).”

What the sources say

• ?Not checked — no full text of the sourcecites De Strooper, 2010 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Nalivaeva et al., 2012 source

In the paper

“Interestingly, β’-cleavage is favored in the neuroprotective Icelandic APP mutation while the canonic β-cleavage at Asp1 is reduced (Kimura et al., 2016).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Kimura et al., 2016 source

In the paper

“Together, these data confirm early studies (Fluhrer et al., 2003; Shi et al., 2003), placing BACE-1 as a prominent Aβ-generating, but also as an occasional Aβ-“degrading” enzyme under some circumstances.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Fluhrer et al., 2003 source
• ?Not checked — no full text of the sourcecites Shi et al., 2003 source

In the paper

“The subcellular location and substrate specificity of γ-secretase may vary depending on the presence of PS1 or PS2 in the complex.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Sannerud et al., 2016 source

In the paper

“Like BACE-1, γ-secretase targets many substrates in addition to APP, with the consequent impact on a vast array of physiological and pathological processes (Haapasalo and Kovacs, 2011).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Haapasalo and Kovacs, 2011 source

In the paper

“sAPPα has been shown to act as a ligand of GABABR1a”

What the sources say

• Not checked yetcites Rice et al., 2019 source

In the paper

“suggesting altogether that TIMP-1 could contribute to AD neuroinflammation and/or downregulate ADAM10 activity”

In the paper

“AICD has gained consensus as signaling molecule that can translocate to the nucleus and regulate the expression of manifold genes, some of them involved in AD pathogenic mechanisms (Kim et al., 2003; Chang et al., 2006), but also in cytoskeleton dynamics, cell cycle control or synaptic plasticity.”

What the sources say

• ?Not checked — no full text of the sourcecites Kim et al., 2003 source
• ?Not checked — no full text of the sourcecites Chang et al., 2006 source

In the paper

“These data linking sAPPα to neuroprotection were later confirmed by studies showing that moderate neuronal overexpression of ADAM10 in transgenic AD mice favored an increase in sAPPα levels and a decrease in Aβ, concomitant with a reduction of deficits in long-term potentiation (LTP) and learning (Postina et al., 2004).”

What the sources say

• Not checked yetcites Postina et al., 2004 source

In the paper

“Clearly, studies are lacking to confirm or refute the idea that a regulatory action of TIMPs on ADAMs could impact on the progression of the disease.”

In the paper

“This is performed by a disintegrin and metalloproteinases (ADAMs) of the metzincin superfamily of metalloproteinases (Rivera et al., 2010; Paschkowsky et al., 2019), in a constitutive (ADAM10) or regulated manner (ADAM17; also known as TACE for TNF-α converting enzyme) (Lammich et al., 1999; Jorissen et al., 2010; Kuhn et al., 2010).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Rivera et al., 2010 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Paschkowsky et al., 2019 source
• ?Not checked — no full text of the sourcecites Lammich et al., 1999 source

In the paper

“Aβ oligomers may be responsible for sAPPα release by cultured neurons and also in vivo”

What the sources say

• ?Not checked — no full text of the sourcecites Rose et al., 2018 source

In the paper

“Presenilins are acidic proteinases [optimum pH 6.3, (Campbell et al., 2003)] that belong to the family of seven transmembrane domain proteins.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Campbell et al., 2003 source

In the paper

“another study in 5xFAD mice, showed mild variations of TIMP-3 mRNA levels at different ages, compared to wild type (Py et al., 2014)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Py et al., 2014

In the paper

“Aβ inhibits ADAM10 in mouse primary neuronal cultures, thus favoring endogenous APP processing by β-secretase (Spilman et al., 2016)”

What the sources say

• ?Not checked — no full text of the sourcecites Spilman et al., 2016 source

In the paper

“instead sAPPβ was reported to induce axonal pruning but not neuronal death, and to interact with DR6 through the more C-terminal E2 domain placed above the β-cleavage site (Olsen et al., 2014)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Olsen et al., 2014 source

In the paper

“While the complex containing PS1 is widely distributed in the cell, a single acidic-dileucine sorting motif present in PS2 directs the γ-secretase complex to late endosomes/lysosomes (Sannerud et al., 2016).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Sannerud et al., 2016 source

In the paper

“The latter can be translocated in the nucleus and engages in transcriptional activities, which are to some extent still controversial in the AD field (reviewed in Pardossi-Piquard and Checler, 2012) (Table 1).”

What the sources say

• ?Not checked — no full text of the sourcecites Pardossi-Piquard and Checler, 2012 source

In the paper

“elevated neuronal immunostaining found in 3xTg transgenic mouse and by increased levels in AD brain homogenates (Hoe et al., 2007)”

What the sources say

• Not checked yetcites Hoe et al., 2007 source

In the paper

“A recent review has identified nearly 40 genes targeted by the AICD in relation with these and other processes (Bukhari et al., 2017)”

What the sources say

• ?Not checked — no full text of the sourcecites Bukhari et al., 2017 source

In the paper

“TIMP-1 expression is highly upregulated in the brain of transgenic 5xFAD mice at early stages of the pathology and remains durably high”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Py et al., 2014

In the paper

“The potential relevance of TIMP-3 in promoting AD pathogenesis is reinforced in this study by the elevated neuronal immunostaining”

What the sources say

• Not checked yetcites Hoe et al., 2007 source

In the paper

“legumain has been involved in numerous pathological settings, including atherosclerosis, osteoporosis, cancer, ischemic stroke, and neurodegenerative diseases (Lunde et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Lunde et al., 2019 source

In the paper

“and preferentially generates Aβ1–40 and a N-terminally truncated Aβ (Aβ2–X)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Bien et al., 2012 source

In the paper

“Legumain, also known as asparagine endopeptidase, is a soluble cysteine proteinase mainly found in endo-lysosomal compartments that provide the optimal functional pH of 6.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Chen et al., 1997 source
• ?Not checked — no full text of the sourcecites Alvarez-Fernandez et al., 1999 source

In the paper

“it could also alter the subcellular location of APP and thus the degree of pathogenicity of proteolytic fragments depending on whether they are mainly generated in endosomes (e.g., C99, Aβ) or in the cell membrane (e.g., sAPPα).”

In the paper

“Using a synthetic peptide mimicking APP/Aβ sequence, it was shown in vitro that meprin-β was able to cleave APP at the β-cleavage site and after the first and second amino acids of the Aβ sequence”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Bien et al., 2012 source

In the paper

“Meprin-β is a type I transmembrane protein of the astacin group of the metzincin superfamily of metalloproteinases (Villa et al., 2003).”

What the sources say

• ?Not checked — no full text of the sourcecites Villa et al., 2003 source

In the paper

“Moreover, decreased APP processing and amyloidogenesis upon MT5-MMP deficiency were concomitant with fewer reactive microglial cells and astrocytes around amyloid plaques, as well as reduced levels of IL-1β and TNF-α (Baranger et al., 2016b, 2017a).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Baranger et al., 2016b
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Baranger et al., 2017a

In the paper

“Aη-γ peptides, potentially generated by a combined action of MT5-MMP and γ-secretase, were not detected, probably revealing a lack of functional interaction between η- and γ-secretase as it is the case with BACE-1, ADAM10 and γ-secretase (Chen et al., 2015; Liu et al., 2019).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Chen et al., 2015 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Liu et al., 2019 source

In the paper

“The function of sAPP95/sAPPη is not yet known, but a recent study showed that it binds GABABR1a, which also acts as a receptor for sAPPα and sAPPβ, resulting in a reduced probability of presynaptic release (Rice et al., 2019).”

What the sources say

• Not checked yetcites Rice et al., 2019 source

In the paper

“When γ-secretase processes C99 into Aβ, the remaining AICD is further cleaved by caspase to generate C31 and JCasp fragments, both of which promote neuronal apoptosis (Bertrand et al., 2001; Madeira et al., 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Bertrand et al., 2001 source
• ?Not checked — no full text of the sourcecites Madeira et al., 2005 source

In the paper

“Despite this, Aβ levels remained stable in HEK293 cells expressing MT3-MMP, probably indicating that MT3-MMP processes APP in cell compartments that do not influence amyloidogenesis.”

In the paper

“Cleavage of APP by caspases generates a membrane bound N-terminal fragment, named APP-Ncas, and an intracellular C-terminal peptide of 31 amino acids, named APP-Ccas or C31.”

In the paper

“Although functional interactions between MT1-MMP and APP/Aβ are not fully understood, it has been shown that the release of sAPP95 by MT1-MMP does not involve BACE-1, but it may involve MMP-2.”

In the paper

“Compared to 5xFAD, 5xFAD/MT5–/– mice showed significantly lower levels of sAPP95, validating our in vitro observations and APP being an in vivo physiological substrate of MT5-MMP (Baranger et al., 2016b).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Baranger et al., 2016b

In the paper

“Aη-α and Aη-β peptides were both detected in human cerebrospinal fluid (CSF) of healthy and AD patients, but no differences in their levels were observed between groups (Willem et al., 2015).”

What the sources say

• Not checked yetcites Willem et al., 2015 source

In the paper

“MT1-MMP upregulation in 5xFAD mice timely and spatially correlates with the increase in C99 levels (Py et al., 2014), thus providing indirect in vivo support for the pro-amyloidogenic features of this MMP described in HEKswe cells (Paumier et al., 2019).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Py et al., 2014
• ?Not checked — no full text of the sourcecites Paumier et al., 2019 source

In the paper

“Transiently expressed MT1-MMP in HEKswe interacts with APP and induces the release of a soluble APP fragment of ∼95 kDa (sAPP95), distinct of sAPPα or sAPPβ generated by α- and β-secretase, respectively.”

In the paper

“The expression of this C-terminal truncated APP in human iPS-derived neurons prevented the production sAPPβ and Aβ, while stimulating α-secretase cleavage.”

In the paper

“Thus, it is possible that lowering cholesterol could increase RHBDL4 activity on full-length APP, with the consequent generation of CTFs and the decrease in Aβ generation (Paschkowsky et al., 2018).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Paschkowsky et al., 2018 source

In the paper

“Mass spectrometry analysis for MT3-MMP cleavage-sites revealed the same VLAN579-M580ISEPR site previously identified for MT1-MMP and 3 other cleavage sites at Ala463-Met464, His622-Ser623 and His685-Gln686 (Higashi and Miyazaki, 2003b), the latter being located in the Aβ sequence, just upstream of the α-cleavage site (Figure 1).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Higashi and Miyazaki, 2003b

In the paper

“Replacing the transmembrane domain (TMD) of BACE-1 by that of MT5-MMP did not prevent BACE-1 complex with γ-secretase and Aβ production, suggesting that motifs other than TMD are involved in the formation of the BACE-1/γ-secretase interactions (Liu et al., 2019).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Liu et al., 2019 source

In the paper

“Another study identified a ∼25 kDa η-CTF in CSF, but in this case the peptide content was higher in AD patients with a PSEN1 familial mutation, in patients with sporadic AD and in Down Syndrome individuals with Alzheimer’s type dementia, compared to age-matched non-demented controls, raising the possibility that η-CTF could be a new disease biomarker (Garcia-Ayllon et al., 2017).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Garcia-Ayllon et al., 2017 source

In the paper

“The mechanism by which MT1-MMP could promote amyloidogenesis is still elusive. Nevertheless, reminiscent of legumain, MT1-MMP cleavage upstream of the β-cleavage site could facilitate β-secretase cleavage of APP and thus the subsequent production of C99 and Aβ.”

In the paper

“Intriguingly, the Willem’s study did not identify MT1-MMP as cleaving at this VLAN504-M505ISEPR/η-site and it was concluded that only MT5-MMP could act as a η-secretase in vivo (Willem et al., 2015).”

What the sources say

• Not checked yetcites Willem et al., 2015 source

In the paper

“By the same time, our group demonstrated that MT5-MMP induced the production of a soluble APP fragment of sAPP95 in HEKswe, concomitant with elevated levels of C99 and Aβ40 (Baranger et al., 2016b).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Baranger et al., 2016b

In the paper

“It is estimated that about 50% of the sAPP95 released after MT1-MMP expression in HEKswe cells results from concerted action with MMP-2, MT1-MMP being in any case the limiting factor in this enzymatic tandem (Paumier et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Paumier et al., 2019 source

In the paper

“This is consistent with the observation that C-terminal truncated forms of Tau show increased polymerization capacity in vitro and are associated with NFTs formation in the brain of AD patients (Gamblin et al., 2003; Rissman et al., 2004).”

What the sources say

• Not checked yetcites Gamblin et al., 2003 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Rissman et al., 2004 source

In the paper

“Most interestingly, it has been proposed that MT1-MMP could also function as a surrogate β-secretase when BACE-1 is inhibited; this is supported by experiments in HEKswe cells where MT1-MMP is able to restore the basal levels of Aβ, almost abolished in the presence of BACE-1 inhibitor IV (or C3) (Paumier et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Paumier et al., 2019 source

In the paper

“Recently, Paschkowsky et al. (2016) showed in HEK cells expressing APP695 that RHBDL4 but not RHDBL1, 2 and 3, cleaves at multiple sites within the ectodomain of APP (Figure 1) and APLP1 and APLP2, generating a N-terminal fragment of ∼70 kDa and different C-terminal fragments whose functions are still unknown.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Paschkowsky et al., 2016 source

In the paper

“It is also noteworthy that AD brains show elevated levels of caspases and that APP fragments resulting from caspase cleavage colocalize with amyloid plaques (Gervais et al., 1999; Lu et al., 2000).”

What the sources say

• ?Not checked — no full text of the sourcecites Gervais et al., 1999 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Lu et al., 2000

In the paper

“η-secretase cleavage of APP generates sAPPη and a residual transmembrane C-terminal APP fragment-η (η-CTF), which accumulates in dystrophic neurites around amyloid plaques in APP/PS1 mice.”

In the paper

“The complementary transmembrane fragment of ∼30 kDa (CTF-30) and C99 are also dramatically increased and their levels highly correlated, suggesting that CTF-30 may be the precursor of C99 (Paumier et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Paumier et al., 2019 source

In the paper

“high cholesterol levels inhibit RHBDL4 activity, which has been correlated with an increase in the formation of Aβ (Paschkowsky et al., 2018).”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Paschkowsky et al., 2018 source

In the paper

“Pre-clinical work has reported TIMP-2 as a possible anti-aging factor as it promotes neuronal plasticity and hippocampal-dependent cognition in aging mice (Castellano et al., 2017).”

What the sources say

• Not checked yetcites Castellano et al., 2017 source

In the paper

“proteinase inhibitors (e.g., TIMPs), which are known to control cell cycle, cell migration or cell fate also independent of anti-proteinase activities (Baranger et al., 2014).”

What the sources say

• ?Not checked — no full text of the sourcecites Baranger et al., 2014 source

In the paper

“in the CSF, two independent studies showed no difference (Mroczko et al., 2014) or increased (Lorenzl et al., 2003a) TIMP-2 levels in AD patients.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Lorenzl et al., 2003a

In the paper

“in the CSF, two independent studies showed no difference (Mroczko et al., 2014) or increased (Lorenzl et al., 2003a) TIMP-2 levels in AD patients.”

What the sources say

• ?Not checked — no full text of the sourcecites Mroczko et al., 2014 source

In the paper

“patients taking statins, a cholesterol-lowering drug, are still less likely to develop the disease (Eckert et al., 2005; Fonseca et al., 2010; Wood et al., 2014).”

What the sources say

• ?Not checked — no full text of the sourcecites Eckert et al., 2005 source
• ?Not checked — no full text of the sourcecites Fonseca et al., 2010 source
• Not checked yetcites Wood et al., 2014 source

In the paper

“A clear link between high cholesterol levels and the pathogenesis of AD has not yet been confirmed”

In the paper

“MT5-MMP can be internalized in endosomes (Wang et al., 2004; Baranger et al., 2017a) and thus promote endosomal APP sorting (Baranger et al., 2017a).”

What the sources say

• ?Not checked — no full text of the sourcecites Wang et al., 2004 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Baranger et al., 2017a

In the paper

“In general, the available literature on proteinase inhibitors and AD remains essentially correlative and the link between both is to date inconclusive or, at best, speculative.”