Dipeptidyl peptidase 4 contributes to Alzheimer’s disease–like defects in a mouse model and is increased in sporadic Alzheimer’s disease brains

Abstract

The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid β peptides in Alzheimer’s disease, is currently being questioned. In addition to full-length amyloid β peptide, several N-terminally truncated fragments of amyloid β peptide could well contribute to Alzheimer’s disease setting and/or progression. Among them, pyroGlu3–amyloid β peptide appears to be one of the main components of early anatomical lesions in Alzheimer’s disease–affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid β, but they appear as the rate-limiting enzymes yielding the Glu3–amyloid β peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3–amyloid β. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3–amyloid β peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3–amyloid β peptide and amyloid β 42–positive plaques and amyloid β 42 load in the triple transgenic Alzheimer’s disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer’s disease–related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer’s disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3–amyloid β peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer’s disease progression. The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid β peptides in Alzheimer’s disease, is currently being questioned. In addition to full-length amyloid β peptide, several N-terminally truncated fragments of amyloid β peptide could well contribute to Alzheimer’s disease setting and/or progression. Among them, pyroGlu3–amyloid β peptide appears to be one of the main components of early anatomical lesions in Alzheimer’s disease–affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid β, but they appear as the rate-limiting enzymes yielding the Glu3–amyloid β peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3–amyloid β. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3–amyloid β peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3–amyloid β peptide and amyloid β 42–positive plaques and amyloid β 42 load in the triple transgenic Alzheimer’s disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer’s disease–related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer’s disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3–amyloid β peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer’s disease progression. Alzheimer’s disease (AD) is the main age-related neurodegenerative disease, the etiology of which remains a matter of questions. One of the main hypotheses referred to as the “amyloid cascade hypothesis” (1Hardy J.A. Higgins G.A. Alzheimer's disease: The amyloid cascade hypothesis.Science. 1992; 256: 184-185Crossref PubMed Scopus (4535) Google Scholar) postulates a key role of amyloid β (Aβ) peptide accumulation (2Checler F. Processing of the b-amyloid precursor protein and its regulation in Alzheimer's disease.J. Neurochem. 1995; 65: 1431-1444Crossref PubMed Scopus (417) Google Scholar) in various brain zones, including those controlling memory, a psychometric paradigm altered in AD and that worsens as the disease progresses. However, the consistent failure of Aβ-centric clinical trials aimed at reducing Aβ load by immunotherapy or pharmacological targeting of its generating enzyme γ-secretase (3Panza F. Lozupone M. Logroscino G. Imbimbo B.P. A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease.Nat. Rev. Neurol. 2019; 15: 73-88Crossref PubMed Scopus (314) Google Scholar, 4Huang Y.M. Shen J. Zhao H.L. Major clinical trials failed the amyloid hypothesis of Alzheimer's disease.J. Am. Geriatr. Soc. 2019; 67: 841-844Crossref PubMed Scopus (17) Google Scholar) casts some doubts about the validity of this hypothesis (5Herrup K. The case for rejecting the amyloid cascade hypothesis.Nat. Neurosci. 2015; 18: 794-799Crossref PubMed Scopus (427) Google Scholar). It remains that, undoubtedly, genetic evidence brought a crystal-clear demonstration that amyloid precursor protein (APP)-linked fragments could participate in the pathology. Several APP-linked catabolites distinct from genuine full-length Aβ (flAβ) were shown to account for some of early lesions of AD-affected brains and could well contribute to the pathology (6Pulina M.V. Hopkins M. Haroutunian V. Greengard P. Bustos V. C99 selectively accumulates in vulnerable neurons in Alzheimer's disease.Alzheimers Dement. 2020; 16: 273-282Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 7Lauritzen I. Pardossi-Piquard R. Bourgeois A. Pagnotta S. Biferi M.G. Barkats M. Lacor P. Klein W. Bauer C. Checler F. Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology.Acta Neuropathol. 2016; 132: 257-276Crossref PubMed Scopus (98) Google Scholar, 8Cavanagh C. Colby-Milley J. Bouvier D. Farso M. Chabot J.G. Quirion R. Krantic S. betaCTF-correlated burst of hippocampal TNFalpha occurs at a very early, pre-plaque stage in the TgCRND8 mouse model of Alzheimer's disease.J. Alzheimers Dis. 2013; 36: 233-238Crossref PubMed Scopus (26) Google Scholar, 9Mondragon-Rodriguez S. Gu N. Manseau F. Williams S. Alzheimer's transgenic model is characterized by very early brain network alterations and beta-CTF fragment accumulation: Reversal by beta-secretase inhibition.Front. Cell Neurosci. 2018; 12: 121Crossref PubMed Scopus (27) Google Scholar, 10Kaur G. Pawlik M. Gandy S.E. Ehrlich M.E. Smiley J.F. Levy E. Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein.Mol. Psychiatry. 2017; 22: 981-989Crossref PubMed Scopus (21) Google Scholar, 11Lauritzen I. Pardossi-Piquard R. Bourgeois A. Becot A. Checler F. Does intraneuronal accumulation of carboxyl-terminal fragments of the amyloid precursor protein trigger early neurotoxicity in Alzheimer's disease?.Curr. Alzheimer Res. 2019; 16: 453-457Crossref PubMed Scopus (25) Google Scholar). Aβ itself is the product of a physiological APP processing (2Checler F. Processing of the b-amyloid precursor protein and its regulation in Alzheimer's disease.J. Neurochem. 1995; 65: 1431-1444Crossref PubMed Scopus (417) Google Scholar, 12Shoji M. Golde T.E. Ghiso J. Cheung T.T. Estus S. Shaffer M. Cai X.D. McKay D.M. Tintner R. Frangione B. Younkin S.G. Production of the Alzheimer amyloid b protein by normal proteolytic processing.Science. 1992; 258: 126-129Crossref PubMed Scopus (1301) Google Scholar, 13Haass C. Hung A.Y. Schlossmacher M.G. Oltersdorf T. Teplow D.B. Selkoe D.J. Normal cellular processing of the b-amyloid precursor protein results in the secretion of the amyloid b peptide and related molecules.Nature. 1993; 695: 109-116Google Scholar) and displays physiological/protective functions (14Sevalle J. Amoyel A. Robert P. Fournie-Zaluski M.C. Roques B. Checler F. Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide.J. Neurochem. 2009; 109: 248-256Crossref PubMed Scopus (84) Google Scholar, 15Castellani R.J. Lee H.G. Perry G. Smith M.A. Antioxidant protection and neurodegenerative disease: The role of amyloid-beta and tau.Am. J. Alzheimers Dis. Other Demen. 2006; 21: 126-130Crossref PubMed Scopus (48) Google Scholar, 16Brothers H.M. Gosztyla M.L. Robinson S.R. The physiological roles of amyloid-beta peptide hint at new ways to treat Alzheimer's disease.Front. Aging Neurosci. 2018; 10: 118Crossref PubMed Scopus (120) Google Scholar) but could be converted into shorter toxic fragments contributing to the pathology (17Dunys J. Valverde A. Checler F. Are N- and C-terminally truncated Abeta species key pathological triggers in Alzheimer's disease?.J. Biol. Chem. 2018; 293: 15419-15428Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Particularly interesting is the pyroGlu3–Aβ (pE3-Aβ) fragment that derives from an N-terminal dipeptide truncation of Aβ yielding a Glu3-Aβ (E3-Aβ) peptide that is subsequently cyclized by glutaminyl cyclase (QC) (18Schilling S. Zeitschel T. M. A. M. B. M. M. W. D. C. T. G. cyclase Abeta and Alzheimer's PubMed Scopus Google Scholar, E. S. processing of amyloid precursor of a role of glutaminyl cyclase in of PubMed Scopus (84) Google Scholar). anatomical and that is in the of into but the demonstration of its key role brought by that its pharmacological blockade or genetic depletion alleviates in an AD mouse model S. S. S. of glutaminyl cyclase, the enzyme for induces behavioral and glutaminyl cyclase the behavioral in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). 4 is an that by as an sequence J. M. J. K. A. J. of the of dipeptidyl peptidase from Chem. PubMed Scopus Google Scholar) and referred to as a dipeptidyl F. T. M. S. in and Scholar). However, that of its main an N-terminal dipeptide this to the N-terminal sequence of the Aβ appears as a enzyme for the rate-limiting of this that in with in A. D. S. M. S. S. of dipeptidyl peptidase and glutaminyl cyclase results in formation of amyloid peptides in 2018; PubMed Scopus Google Scholar) and that could as an AD E. C. A Alzheimer's 2018; PubMed Google Scholar, J. D. J. dipeptidyl treat 2020; PubMed Scopus Google Scholar). Here, we by that the N-terminal dipeptide of and in that a the of by that the pharmacological blockade of by its alterations in from with the APP the Furthermore, and the of plaques and in triple transgenic AD mouse establish that genetic reduction and/or by the and in mice. we a and of activity in a of sporadic AD brains. our data the that could contribute to AD pathology. that with the N-terminal of Aβ A. J. P. N. C. P. K. J. S. J. M. of new for and 42 amyloid b to the of and the of sporadic Alzheimer's disease and amyloid PubMed Google we that A the of by (14Sevalle J. Amoyel A. Robert P. Fournie-Zaluski M.C. Roques B. Checler F. Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide.J. Neurochem. 2009; 109: 248-256Crossref PubMed Scopus (84) Google Scholar). Here, we as a that, as one of the main enzymes S. J. S. enzymes in Alzheimer's 18: PubMed Scopus Google Scholar, The Alzheimer's we J. Alzheimers Dis. Google with its and Furthermore, we the of the Roques B.P. Fournie-Zaluski M.C. of the and Chem. PubMed Scopus Google C. A. N. S. C. Fournie-Zaluski M.C. Roques B.P. of in A to the of the and of this Chem. PubMed Scopus Google and J.A. S.G. R. W. with the dipeptidyl peptidase in and in PubMed Scopus Google Scholar). and but the of we an of and data that and but contribute to the N-terminal truncation of and that these the of to from we that peptide into the N-terminal dipeptide of A and the increased with and by the J.A. S.G. R. W. with the dipeptidyl peptidase in and in PubMed Scopus Google Scholar) and the of on spine of hippocampal with or in The spine and of the of the various as by a of APP and and a of and in the alterations in were by with the and peptidase A for the of Dis. Res. 2006; PubMed Scopus Google and the that of could account for the of in these this we whether functional and they Our data that in that is in from these and activity It is of to that our that could and that by A. J. T. D. S. Roques B.P. M. Checler F. Aminopeptidase A contributes to biochemical, anatomical and in Alzheimer's disease (AD) mouse model and is increased at early stage in sporadic AD Neuropathol. PubMed Scopus Google Scholar). this of data that contributes to the alterations in an AD model. to and activity by several targeting as well as an to a sequence examined to and activity in Among them, one sequence its the of by about with A and we the and with to that of in the of the of mouse brains triggers an about reduction of activity in mouse brain and examined the and anatomical of reduction in or at the of with the or the of the of plaques A and and we a of in with as at this and were in the Aβ in an from in and However, Aβ species were in these and to the influence of with we aimed at whether of could we that an of triggers a reduction of about of activity the of of to the one by and this could blockade of Thus, we that undergoes in P. Checler F. A of the and of and in 1993; PubMed Scopus Google Scholar) that could account for and at an plaques at the of Thus, the of the of plaques and from we a consistent reduction of plaques A and and In with a genuine reduction of plaques in a in the from our genetic and pharmacological that formation and Aβ aggregation in mice. whether activity could memory and learning in we the mouse model that several of AD that memory and S. A. G. Golde T.E. R. R. F. model of Alzheimer's disease with plaques and and Full Text Full Text PDF PubMed Scopus Google Scholar). learning the and that considered as to memory deficits in these M.A. of deficits in the mouse model of Alzheimer's Res. 2015; PubMed Scopus Google to the influence of genetic and pharmacological reduction of were in learning as by a to the in the these alterations is by the in the of that in in at in the to with that pharmacological blockade of the to the in the a paradigm that altered in the of the of in in activity or as by the and It that is in in brains of with sporadic and AD E. K. J. P. A. E. D. K. amyloid peptide in sporadic and Alzheimer's PubMed Scopus Google Scholar). Thus, to our we that be an activity of in AD-affected brains. Here, we activity in of and from sporadic AD at a activity in AD brains in appears to be AD at and to to at The main of our is that the reduction of could be in the of It is by of in and in the N-terminal dipeptide of of in the of in neurons that alterations of pharmacological blockade of a normal genetic and pharmacological plaques and load in from brains. and rescue learning and memory this consistent network of evidence that could contribute to the of in It be that as the rate-limiting enzyme yielding to cyclization by in A. D. S. M. S. S. of dipeptidyl peptidase and glutaminyl cyclase results in formation of amyloid peptides in 2018; PubMed Scopus Google Scholar). as to interfere with J. D. J. dipeptidyl treat 2020; PubMed Scopus Google Scholar). of with a for and in and related A Neurosci. 2017; PubMed Scopus Google Scholar). is to the of to J. a dipeptidyl deficits and pathology in the mouse model of Alzheimer's 2017; PubMed Scopus Google Scholar) including M. C. R. F. F. G. of dipeptidyl in Alzheimer's PubMed Scopus Google Scholar, S. M. J. A. P. Zhao G. learning and memory deficits and by the 2019; PubMed Scopus (21) Google Scholar). is a peptide which an N-terminal dipeptide that the of is one of the of and in of clinical 2020; PubMed Scopus Google Scholar). is in the is in the brain and in the and A new strategy for disease the The 2017; PubMed Scopus Google Scholar). is in with AD as well as in AD mouse brain S. M. J. A. P. Zhao G. learning and memory deficits and by the 2019; PubMed Scopus (21) Google Scholar). Furthermore, shown that triggers and that its its M. C. R. F. F. G. of dipeptidyl in Alzheimer's PubMed Scopus Google Scholar, S. M. J. A. P. Zhao G. learning and memory deficits and by the 2019; PubMed Scopus (21) Google Scholar). and deficits in several AD mouse J. a dipeptidyl deficits and pathology in the mouse model of Alzheimer's 2017; PubMed Scopus Google Scholar, M. C. R. F. F. G. of dipeptidyl in Alzheimer's PubMed Scopus Google Scholar, S. M. J. A. P. Zhao G. learning and memory deficits and by the 2019; PubMed Scopus (21) Google Scholar) including the S. M. J. A. P. Zhao G. learning and memory deficits and by the 2019; PubMed Scopus (21) Google Scholar). Our data that, could participate to AD pathology by targeting In AD mouse several anatomical and functional including and dysfunction S. Gu N. Manseau F. Williams S. Alzheimer's transgenic model is characterized by very early brain network alterations and beta-CTF fragment accumulation: Reversal by beta-secretase inhibition.Front. Cell Neurosci. 2018; 12: 121Crossref PubMed Scopus (27) Google Scholar, precursor protein and dysfunction in Alzheimer's disease: in a J. 2017; PubMed Scopus Google Scholar, R. Gu N. C. J. Chabot J.G. Quirion R. Krantic S. Williams S. in hippocampal network and Abeta in a mouse model of Alzheimer's J. Neurosci. 2013; PubMed Scopus Google Scholar) shown to early and of Aβ I. Pardossi-Piquard R. Bourgeois A. Pagnotta S. Biferi M.G. Barkats M. Lacor P. Klein W. Bauer C. Checler F. Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology.Acta Neuropathol. 2016; 132: 257-276Crossref PubMed Scopus (98) Google Scholar, A. I. T. Bauer C. Checler F. Pardossi-Piquard R. Intraneuronal accumulation of C99 contributes to and learning deficits in and 2018; PubMed Scopus Google Scholar) for some of them, by γ-secretase I. Pardossi-Piquard R. Bourgeois A. Pagnotta S. Biferi M.G. Barkats M. Lacor P. Klein W. Bauer C. Checler F. Intraneuronal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-independent lysosomal-autophagic pathology.Acta Neuropathol. 2016; 132: 257-276Crossref PubMed Scopus (98) Google Scholar). evidence that the fragment of APP could account for these I. Pardossi-Piquard R. Bourgeois A. Becot A. Checler F. Does intraneuronal accumulation of carboxyl-terminal fragments of the amyloid precursor protein trigger early neurotoxicity in Alzheimer's disease?.Curr. Alzheimer Res. 2019; 16: 453-457Crossref PubMed Scopus (25) Google Scholar). However, at stage of an contribution to learning and memory The demonstration of this brought by the of and A. I. T. Bauer C. Checler F. Pardossi-Piquard R. Intraneuronal accumulation of C99 contributes to and learning deficits in and 2018; PubMed Scopus Google Scholar). The accumulation of C99 they of Aβ to the of A. I. T. Bauer C. Checler F. Pardossi-Piquard R. Intraneuronal accumulation of C99 contributes to and learning deficits in and 2018; PubMed Scopus Google and early the learning and memory defects. Our data that these alterations of could be for by we that genetic reduction and pharmacological blockade of plaques and is to the reduction of Thus, shown that very of to as E. S. B. K. amyloid behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google its aggregation A. D. S. M. S. S. of dipeptidyl peptidase and glutaminyl cyclase results in formation of amyloid peptides in 2018; PubMed Scopus Google and the of It be that alterations by genetic or pharmacological of could be by the that triggers a reduction of the enzyme activity but by a A. D. F. J. A. W. S. K. G. J. R. of an dipeptidyl in PubMed Scopus Google Scholar). is that activities in Aβ truncation could One could be the Thus, this enzyme displays a for as the N-terminal of Aβ F. T. M. S. in and Scholar). hypothesis is by our (14Sevalle J. Amoyel A. Robert P. Fournie-Zaluski M.C. Roques B. Checler F. Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide.J. Neurochem. 2009; 109: 248-256Crossref PubMed Scopus (84) Google Scholar) that the of cellular Furthermore, our that the and rescue and plaques and and memory in A. J. T. D. S. Roques B.P. M. Checler F. Aminopeptidase A contributes to biochemical, anatomical and in Alzheimer's disease (AD) mouse model and is increased at early stage in sporadic AD Neuropathol. PubMed Scopus Google Scholar). and of that the enzymes Thus, the alterations could be to and It be that we shown that the reduction of in alleviates memory deficits in is increased in sporadic AD-affected but this occurs early at and to at data well with that is in AD brain neurons and is with plaques H.G. G. J. peptidase which roles in Alzheimer disease (AD) is in AD brain neurons and with amyloid 2018; PubMed Scopus (17) Google Scholar) but at the stage in and of with AD C. N. P. P. J. Checler F. of alterations of on the of in Alzheimer's disease.J. Neurochem. PubMed Scopus Google Scholar). The of with the of plaques and one that the could well the of its aggregation and the of well with the that very of could as a of aggregation and E. S. B. K. amyloid behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and that of to hippocampal in transgenic A. W. S. A. C. S. R. R. E. M. A. S. hippocampal in transgenic of truncated Abeta is by Neurosci. PubMed Scopus Google Scholar). Thus, could be to a by which AD anatomical lesions from for various with or for with or the were addition of and were to Aβ peptides were with on a in an data were with a in the Aβ fragments were were in were in and to for in to Aβ by The Alzheimer's we J. Alzheimers Dis. Google Scholar, N. S. S. for of Alzheimer disease.J. Neuropathol. Neurol. PubMed Scopus Google with or and at were with of and and with a of A. J. P. N. C. P. K. J. S. J. M. of new for and 42 amyloid b to the of and the of sporadic Alzheimer's disease and amyloid PubMed Google Scholar) and protein A were with and with and to were and with the by D. at a with a and were the hippocampal were from to were to and were in and into the and were on in the and were with for and were at with for were for at a of were on the and with the and on an of from with and at The of spine and as S. A. S. J. B. N. C. at Scopus Google Scholar, C. in we from 2016; PubMed Scopus Google Scholar). were in of and in were and were by activity as in activity hippocampal were with of and in were in the for and with the in for were with in were in and on the with the and the hippocampal were in with and were by one and one for with for The at in were in were in at a of were for with with for with and for with The of and were with and for with the of were with and with the with the which well with the at and to the in were in activity in of with or the as the in the a of at and as C. N. P. P. J. Checler F. of alterations of on the of in Alzheimer's disease.J. Neurochem. PubMed Scopus Google Scholar). S. A. G. Golde T.E. R. R. F. model of Alzheimer's disease with plaques and and Full Text Full Text PDF PubMed Scopus Google Scholar) and were from by were with a and were to and were in with the of and by the of and and by and were as M. E. T. J. Bauer C. I. Checler F. The hippocampal and memory by of the in Alzheimer Psychiatry. 2017; 22: PubMed Scopus Google Scholar). were Cell and in the with an R. A. S. V. R. C. Checler F. M. is by of the Biol. Chem. 2017; Full Text Full Text PDF PubMed Scopus (27) Google Scholar) were the of the and were in the the mouse the to and were by with a of and were into the with of at the in A and of by a by at a of for a for a of of for and activity as learning and memory were a I. M. in an with 2019; PubMed Scopus Google Scholar). to 4 on a to a a of the being for memory with a in which a of to the Several were including the to the of and in the of the in a with an and in a by as A. I. T. Bauer C. Checler F. Pardossi-Piquard R. Intraneuronal accumulation of C99 contributes to and learning deficits in and 2018; PubMed Scopus Google Scholar). were with the of on a model as A. I. T. Bauer C. Checler F. Pardossi-Piquard R. Intraneuronal accumulation of C99 contributes to and learning deficits in and 2018; PubMed Scopus Google Scholar). trials were a of for and were by an in the of the is or with or with pharmacological were as brains were in and with a at a of were with and at 4 with a amyloid to 42 that with and or with several were for with an were with the brain were from the brain were in with the of and as well as the and In with the were by the or in were and and is in were of in and were by a and for activity as from and or hippocampal were in a of as R. I. Bauer C. G. Robert P. Checler F. of genetic on in triple transgenic AD Alzheimer Res. 2016; PubMed Scopus Google Scholar). were by a at 4 were in 4 and were brought to by addition of referred to as the and peptides were in as I. Pardossi-Piquard R. Bauer C. E. S. P. P. V. J. Checler F. The fragment of but is a key to early intraneuronal lesions in mouse Neurosci. PubMed Scopus Google Scholar). and were by and the to the spine activities were by and behavioral were normal of and of were by normal and and by with and by of and and the of and were considered by and with by data were to and and we the The and of plaques were by on and to an of for The activity in the with data the and in the The that they of with the of this The for of mice. the for the of for a to the and the Alzheimer The and at and The for A. T. and F. C. A. T. D. C. and M. C. A. V. A. J. M. and F. C. and J. D. and F. C. F. C. F. C. F. C. F. C. with and

Topics & Concepts