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arxiv: 2510.02824 · v2 · submitted 2025-10-03 · 🧬 q-bio.NC

Pyk2 plays a critical role in synaptic dysfunction during the early stages of Alzheimer's disease

Quentin Rodriguez (GIN , UGA) , Floriane Payet (GIN , Karina Vargas-Baron (GIN , Eve Borel (GIN , Fabien Lant\'e (GIN , Sylvie Boisseau (GIN , B\'eatrice Blot (GIN
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Jean-Antoine Girault (IFM - Inserm U1270 - SU INSERM) Alain Buisson (GIN
This is my paper

Pith reviewed 2026-05-18 10:37 UTC · model grok-4.3

classification 🧬 q-bio.NC
keywords Pyk2Alzheimer's diseasesynaptic dysfunctionamyloid-betaTauhippocampal hyperactivitysynaptic loss
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The pith

Deleting Pyk2 prevents amyloid-beta induced hippocampal hyperactivity and synaptic loss while decreasing Tau at synapses.

A machine-rendered reading of the paper's core claim, the machinery that carries it, and where it could break.

This paper investigates the role of the tyrosine kinase Pyk2 in the early synaptic changes seen in Alzheimer's disease. It shows that removing Pyk2 from mice stops the overactivity of hippocampal neurons and the loss of synapses triggered by amyloid-beta oligomers. The study also finds that Pyk2 binds to Tau and helps position it at synapses, a step linked to disease progression. A sympathetic reader would care because these synaptic problems occur early, before widespread neuron death, so blocking Pyk2 might offer a way to intervene sooner. The work uses genetic knockouts, cell cultures, and biochemical assays to link Pyk2 to these processes.

Core claim

Pyk2 contributes to hippocampal neuronal hyperactivity and synaptic loss, two early events in Alzheimer's disease pathogenesis. It is also involved in Tau synaptic localization, a process known to be detrimental in Alzheimer's disease. Genetic deletion of Pyk2 prevented amyloid-beta oligomer-induced hippocampal neuronal hyperactivity and synaptic loss. Overexpression of Pyk2 in neurons decreased dendritic spine density independently of its autophosphorylation or kinase activity, but through its proline-rich motif 1. Furthermore, Pyk2 interacted with Tau in synapses, while Pyk2 deletion decreased Tau synaptic localization in the hippocampus.

What carries the argument

Pyk2 tyrosine kinase acting through its proline-rich motif 1 to mediate synaptic loss and interact with Tau in synapses.

If this is right

  • Pyk2 serves as a promising therapeutic target for early intervention in Alzheimer's disease.
  • Inhibiting Pyk2 could reduce neuronal hyperactivity caused by amyloid-beta.
  • Blocking Pyk2 decreases harmful Tau presence in synapses.
  • The effects of Pyk2 on spine density are independent of its kinase activity.

Where Pith is reading between the lines

These are editorial extensions of the paper, not claims the author makes directly.

  • The mechanism might extend to other tau-related neurodegenerative conditions.
  • Targeting the proline-rich motif specifically could lead to new drug candidates with fewer side effects.
  • Gene variants in PTK2B may affect Alzheimer's risk via these synaptic pathways.

Load-bearing premise

That amyloid-beta oligomer exposure in Pyk2 knockout mouse hippocampal slices and cultured neurons faithfully models the early synaptic dysfunction in human Alzheimer's disease.

What would settle it

Examining synaptic activity and spine density in human neurons derived from Alzheimer's patients after Pyk2 inhibition to see if the protective effects hold.

Figures

Figures reproduced from arXiv: 2510.02824 by Alain Buisson (GIN, B\'eatrice Blot (GIN, Eve Borel (GIN, Fabien Lant\'e (GIN, Floriane Payet (GIN, INSERM), Jean-Antoine Girault (IFM - Inserm U1270 - SU, Karina Vargas-Baron (GIN, Quentin Rodriguez (GIN, Sylvie Boisseau (GIN, UGA).

Figure 1
Figure 1. Figure 1: Pyk2 is involved in Aβo-induced hyperactivity of hippocampal neurons in 1-month￾old mice. A) Representative traces of sEPSCs recorded in whole-cell mode from hippocampal neurons clamped at -60 mV in 1-month-old WT and APP/PS1-21 mice. B) Histograms showing the frequency and amplitude of sEPSCs recorded from pyramidal neurons in the CA1 region of the hippocampus in 1-month-old WT and APP/PS1-21 mice (n = 10… view at source ↗
Figure 2
Figure 2. Figure 2: During neuronal hyperactivity, Pyk2 is phosphorylated on its tyrosine 402. A, C) [PITH_FULL_IMAGE:figures/full_fig_p019_2.png] view at source ↗
read the original abstract

Background: The locus of the gene PTK2B encoding the tyrosine kinase Pyk2 has been associated with the risk of late-onset Alzheimer's disease, the predominant form of dementia. Pyk2 is primarily expressed in neurons where it is involved in excitatory neurotransmission and synaptic functions. Although previous studies have implicated Pyk2 in amyloid-beta and Tau pathologies of Alzheimer's disease, its exact role remains unresolved, with evidence showing both detrimental and protective effects in mouse models. Here, we investigate the role of Pyk2 in hippocampal hyperactivity, Tau synaptic localization and synaptic loss associated with Alzheimer's disease-related alterations occurring in the early stages of the disease. Methods: Pyk2's involvement in amyloid-beta oligomer-induced hippocampal neuronal hyperactivity was investigated using whole-cell patch clamp in hippocampal slices from WT and Pyk2 KO mice. Various Pyk2 mutants were overexpressed in cultured cortical neurons to study Pyk2's role in synaptic loss. Pyk2 and Tau interaction was assessed with bimolecular fluorescence complementation assays in cultured neurons and co-immunoprecipitation in mouse cortex. To evaluate the impact of Pyk2 on Tau expression in synapses, cellular fractionation was performed on hippocampi from WT and Pyk2 KO mice. Results: Genetic deletion of Pyk2 prevented amyloid-beta oligomer-induced hippocampal neuronal hyperactivity and synaptic loss. Overexpression of Pyk2 in neurons decreased dendritic spine density independently of its autophosphorylation or kinase activity, but through its proline-rich motif 1. Furthermore, Pyk2 interacted with Tau in synapses, while Pyk2 deletion decreased Tau synaptic localization in the hippocampus. Conclusions: Pyk2 contributes to hippocampal neuronal hyperactivity and synaptic loss, two early events in Alzheimer's disease pathogenesis. It is also involved in Tau synaptic localization, a process known to be detrimental in Alzheimer's disease. These findings highlight Pyk2 as a critical player in Alzheimer's disease pathophysiology and suggest its potential as a promising therapeutic target for early intervention.

Editorial analysis

A structured set of objections, weighed in public.

Desk editor's note, referee report, simulated authors' rebuttal, and a circularity audit. Tearing a paper down is the easy half of reading it; the pith above is the substance, this is the friction.

Referee Report

2 major / 2 minor

Summary. The manuscript examines the role of the tyrosine kinase Pyk2 (encoded by PTK2B) in early Alzheimer's disease synaptic pathology. Using Pyk2 knockout mice, it reports that genetic deletion of Pyk2 blocks amyloid-beta oligomer-induced hippocampal neuronal hyperactivity (whole-cell patch clamp in acute slices) and prevents synaptic loss in cultured neurons. Overexpression of Pyk2 or mutants in neurons shows that spine density reduction depends on the proline-rich motif 1 but not on kinase activity or autophosphorylation. Biochemical and imaging assays (BiFC, co-IP, cellular fractionation) demonstrate that Pyk2 interacts with Tau at synapses and that Pyk2 deletion reduces Tau synaptic localization in the hippocampus.

Significance. If the central experimental contrasts hold, the work would strengthen the link between a known AD risk locus and two early, load-bearing features of AD pathogenesis—neuronal hyperactivity and synaptic loss—while also implicating Pyk2 in synaptic Tau localization. The multi-method approach (electrophysiology, spine imaging, protein interaction assays, and fractionation) provides convergent evidence that could support Pyk2 as a therapeutic target for early intervention, consistent with the genetic association of PTK2B with late-onset AD.

major comments (2)
  1. [Methods] Methods (Aβ oligomer exposure in slices and cultures): The claim that Pyk2 deletion prevents early AD-related synaptic dysfunction rests on acute exogenous Aβ oligomer application. The manuscript provides no direct validation or side-by-side comparison demonstrating that the short-term oligomer concentrations and species used here produce synaptic changes comparable to those in chronic, pre-plaque in-vivo models (e.g., APP/PS1 mice) or prodromal human AD tissue. This modeling assumption is load-bearing for interpreting the KO rescue as relevant to early-stage disease.
  2. [Results] Results (patch-clamp and spine-density data): The abstract states consistent directional effects across genotypes, yet the provided text does not report raw traces, full statistical tables (including exact p-values, n per condition, and exclusion criteria), or power calculations. Without these, the magnitude and reliability of the hyperactivity and spine-loss rescue cannot be fully assessed.
minor comments (2)
  1. [Methods] The abstract and methods should explicitly state the source, preparation protocol, and final concentration range of the Aβ oligomers used, as well as any quality-control steps (e.g., oligomer size distribution).
  2. [Results] Figure legends and results text should clarify whether the BiFC and co-IP experiments were performed in the presence or absence of Aβ oligomers, as this affects interpretation of the Pyk2–Tau interaction in the disease context.

Simulated Author's Rebuttal

2 responses · 0 unresolved

We thank the referee for their constructive and detailed comments, which have identified important areas for improving the clarity and rigor of our manuscript on the role of Pyk2 in early Alzheimer's disease synaptic pathology. We address each major comment below and outline the revisions we will make.

read point-by-point responses

  1. Referee: [Methods] Methods (Aβ oligomer exposure in slices and cultures): The claim that Pyk2 deletion prevents early AD-related synaptic dysfunction rests on acute exogenous Aβ oligomer application. The manuscript provides no direct validation or side-by-side comparison demonstrating that the short-term oligomer concentrations and species used here produce synaptic changes comparable to those in chronic, pre-plaque in-vivo models (e.g., APP/PS1 mice) or prodromal human AD tissue. This modeling assumption is load-bearing for interpreting the KO rescue as relevant to early-stage disease.

    Authors: We agree that establishing the relevance of acute Aβ oligomer application to chronic, pre-plaque models is important for contextualizing our findings. Our approach follows standard methods for dissecting early synaptic mechanisms, but we acknowledge the lack of direct side-by-side validation in the current manuscript. In the revised version, we will expand the Discussion to include explicit comparisons with published data from APP/PS1 and other transgenic models at pre-plaque stages, citing studies that report comparable neuronal hyperactivity and synaptic loss using similar oligomer preparations. We will also add a limitations paragraph noting that while acute models do not fully recapitulate chronic pathology, the convergent results across electrophysiology, imaging, and biochemical assays support mechanistic relevance to early AD. New comparative experiments are beyond the scope of this revision. revision: partial

  2. Referee: [Results] Results (patch-clamp and spine-density data): The abstract states consistent directional effects across genotypes, yet the provided text does not report raw traces, full statistical tables (including exact p-values, n per condition, and exclusion criteria), or power calculations. Without these, the magnitude and reliability of the hyperactivity and spine-loss rescue cannot be fully assessed.

    Authors: We apologize for the incomplete reporting of statistical details and raw data in the initial submission. This omission limits full assessment of the results. In the revised manuscript, we will add complete statistical tables reporting exact p-values, n values for each condition, exclusion criteria, and power calculations where relevant. Representative raw traces from the whole-cell patch-clamp recordings will be included in the supplementary figures, along with the full spine-density datasets. These additions will enable rigorous evaluation of the effect sizes and reliability of the Pyk2-dependent rescues. revision: yes

Circularity Check

0 steps flagged

No circularity: experimental contrasts between genotypes and conditions are independent of inputs

full rationale

The paper reports direct experimental results from patch-clamp recordings in hippocampal slices, spine density measurements in cultured neurons, bimolecular fluorescence complementation, co-immunoprecipitation, and cellular fractionation comparing WT versus Pyk2 KO mice under Aβ oligomer exposure. No equations, fitted parameters, predictions derived from subsets of the same data, or self-citation chains are present that would reduce any central claim to a definitional or statistical tautology. The derivation chain consists of standard wet-lab contrasts whose validity rests on external controls and replication rather than internal re-labeling of inputs.

Axiom & Free-Parameter Ledger

0 free parameters · 2 axioms · 0 invented entities

The central claims rest on standard domain assumptions about model validity rather than new free parameters or invented entities.

axioms (2)
  • domain assumption Amyloid-beta oligomer exposure in acute hippocampal slices from Pyk2 KO mice recapitulates early synaptic dysfunction in human Alzheimer's disease.
    This premise is required to translate the observed prevention of hyperactivity and synaptic loss to human disease relevance.
  • domain assumption Dendritic spine density in cultured cortical neurons and Tau localization in fractionated hippocampal tissue reflect in vivo synaptic integrity.
    Invoked when interpreting overexpression and fractionation results as evidence of synaptic loss and Tau mislocalization.

pith-pipeline@v0.9.0 · 5960 in / 1392 out tokens · 40959 ms · 2026-05-18T10:37:59.539958+00:00 · methodology

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Reference graph

Works this paper leans on

60 extracted references · 60 canonical work pages

  1. [1]

    Global estimates on the number of persons across the Alzheimer’s disease continuum

    Gustavsson A, Norton N, Fast T, Frölich L, Georges J, Holzapfel D, et al. Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimers Dement. 2023 Feb;19(2):658–70

    work page 2023

  2. [2]

    World Alzheimer Report 2015

    Prince M, Wimo A, Guerchet M, Ali GC, Wu YT, Prina M. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends

    work page 2015

  3. [3]

    Role of Genes and Environments for Explaining Alzheimer Disease

    Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of Genes and Environments for Explaining Alzheimer Disease. Arch Gen Psychiatry. 2006 Feb 1;63(2):168

    work page 2006

  4. [4]

    Meta - analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease

    European Alzheimer’s Disease Initiative (EADI), Genetic and Environmental Risk in Alzheimer’s Disease (GERAD), Alzheimer’s Disease Genetic Consortium (ADGC), Cohorts for Heart and Aging Research in Geno mic Epidemiology (CHARGE), Lambert JC, Ibrahim -Verbaas CA, et al. Meta - analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheim...

    work page 2013

  5. [5]

    Genome -Wide Association Meta -analysis of Neuropathologic Features of Alzheimer’s Disease and Related Dementias

    Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelma n M, Myers AJ, et al. Genome -Wide Association Meta -analysis of Neuropathologic Features of Alzheimer’s Disease and Related Dementias. Gibson G, editor. PLoS Genet. 2014 Sep 4;10(9):e1004606

    work page 2014

  6. [6]

    Common variant in PTK2B is associated with late-onset Alzheimer’s disease: A replication study and meta -analyses

    Li YQ, Tan MS, Wang HF, Tan CC, Zhang W, Zheng ZJ, et al. Common variant in PTK2B is associated with late-onset Alzheimer’s disease: A replication study and meta -analyses. Neurosci Lett. 2016 May 16;621:83–7

    work page 2016

  7. [7]

    Genetic meta -analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates A β, tau, immunity and lipid processing

    Kunkle BW, Grenier -Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta -analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates A β, tau, immunity and lipid processing. Nat Genet. 2019 Mar;51(3):414–30

    work page 2019

  8. [8]

    Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes

    Schwartzentruber J, Cooper S, Liu JZ, Barrio-Hernandez I, Bello E, Kumasaka N, et al. Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes. Nat Genet. 2021 Mar;53(3):392–402

    work page 2021

  9. [9]

    Fyn inhibition rescues established memory and synapse loss in Alzheimer mice: Fyn Inhibition by AZD0530

    Kaufman AC, Sa lazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, et al. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice: Fyn Inhibition by AZD0530. Ann Neurol. 2015 Jun;77(6):953–71

    work page 2015

  10. [10]

    Pyk2 Signal ing through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss

    Lee S, Salazar SV, Cox TO, Strittmatter SM. Pyk2 Signal ing through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss. J Neurosci. 2019 Mar 6;39(10):1910–29

    work page 2019

  11. [11]

    Alzheimer’s Disease Risk Factor Pyk2 Mediates Amyloid -β-Induced Synaptic Dysfunction and Loss

    Salazar SV, Cox TO, Lee S, Brody AH, Chyung AS, Haas LT, et al. Alzheimer’s Disease Risk Factor Pyk2 Mediates Amyloid -β-Induced Synaptic Dysfunction and Loss. J Neurosci. 2019 Jan 23;39(4):758–72

    work page 2019

  12. [12]

    PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer’s disease

    Giralt A, de Pins B, Cifuentes -Díaz C, López -Molina L, Farah AT, Tible M, et al. PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer’s disease. Experimental Neurol ogy. 2018 Sep;307:62–73

    work page 2018

  13. [13]

    Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology

    Dourlen P, Fernandez -Gomez FJ, Dupont C, Grenier -Boley B, Bellenguez C, Obriot H, et al. Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology. Mol Psychiatry. 2017 Jun;22(6):874–83

    work page 2017

  14. [14]

    Pyk2 is a Novel Tau Tyrosine Kinase that is Regulated by the Tyrosine Kinase Fyn

    Li C, Götz J. Pyk2 is a Novel Tau Tyrosine Kinase that is Regulated by the Tyrosine Kinase Fyn. Reddy PH, editor. JAD. 2018 Jun 8;64(1):205–21. 42

    work page 2018

  15. [15]

    Phosphorylation of tau by glycog en synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules

    Lovestone S, Hartley CL, Pearce J, Anderton BH. Phosphorylation of tau by glycog en synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules. Neuroscience. 1996 Aug;73(4):1145–57

    work page 1996

  16. [16]

    Glycogen Synthase Kinase 3β Is Tyrosine Phosphorylated by PYK2

    Hartigan JA, Xiong WC, Johnson GVW. Glycogen Synthase Kinase 3β Is Tyrosine Phosphorylated by PYK2. Biochemical and Biophysical Research Communications. 2001 Jun;284(2):485–9

    work page 2001

  17. [17]

    Non-canonical pathway induced by Wnt3a regulates β-catenin via Pyk2 in differen tiating human neural progenitor cells

    Narendra Talabattula VA, Morgan P, Frech MJ, Uhrmacher AM, Herchenröder O, Pützer BM, et al. Non-canonical pathway induced by Wnt3a regulates β-catenin via Pyk2 in differen tiating human neural progenitor cells. Biochem Biophys Res Commun. 2017 Sep 9;491(1):40–6

    work page 2017

  18. [18]

    Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of t auopathy

    Brody AH, Nies SH, Guan F, Smith LM, Mukherjee B, Salazar SA, et al. Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of t auopathy. Mol Neurodegeneration. 2022 May 3;17(1):32

    work page 2022

  19. [19]

    Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD

    Dickerson BC, Salat DH, Greve DN, Chua EF, Rand -Giovannetti E, Rentz DM, et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology. 2005 Aug 9;65(3):404–11

    work page 2005

  20. [20]

    Alterations in memory networks in mild cognitive impairment and Alzheimer’s disease: an independent component analysis

    Celone KA, Calhoun VD, Dickerson BC, Atri A, Chua EF, Miller SL, et al. Alterations in memory networks in mild cognitive impairment and Alzheimer’s disease: an independent component analysis. J Neurosci. 2006 Oct 4;26(40):10222–31

    work page 2006

  21. [21]

    Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline

    Miller SL, Fenstermacher E, Bates J, Blacker D, Sperling RA, Dickerson BC. Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline. J Neurol Neurosurg Psychiatry. 2008 Jun;79(6):630–5

    work page 2008

  22. [22]

    Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults

    Gallego-Rudolf J, Wi esman AI, Pichet Binette A, Villeneuve S, Baillet S, PREVENT -AD Research Group. Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults. Nat Neurosci. 2024 Nov;27(11):2130–7

    work page 2024

  23. [23]

    Synaptic change in the posterior cingulate gyrus in the progression of Alzheimer’s disease

    Scheff SW, Price DA, Ansari MA, Roberts KN, Schmitt FA, Ikonomovic MD, et al. Synaptic change in the posterior cingulate gyrus in the progression of Alzheimer’s disease. J Alzheimers Dis. 2015;43(3):1073–90

    work page 2015

  24. [24]

    Astrocyte – neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade

    Paumier A, Boisseau S, Jacquier -Sarlin M, Pern et-Gallay K, Buisson A, Albrieux M. Astrocyte – neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade. Brain. 2022 Mar 29;145(1):388–405

    work page 2022

  25. [25]

    CAKbeta/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus

    Huang Y, Lu W, Ali DW, Pelkey KA, Pitcher GM, Lu YM, et al. CAKbeta/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus. Neuron. 2001 Feb;29(2):485–96

    work page 2001

  26. [26]

    Postsynaptic clustering and activation of Pyk2 by PSD-95

    Bartos JA, Ulrich JD, Li H, Beazely MA, Chen Y, Macdonald JF, et al. Postsynaptic clustering and activation of Pyk2 by PSD-95. J Neurosci. 2010 Jan 13;30(2):449–63

    work page 2010

  27. [27]

    Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression

    Hsin H, Kim MJ, Wang CF, Sheng M. Proline-rich tyrosine kinase 2 regulates hippocampal long-term depression. J Neurosci. 2010 Sep 8;30(36):11983–93

    work page 2010

  28. [28]

    Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology

    Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, et al. Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Reports. 2006 Sep;7(9):940–6. 43

    work page 2006

  29. [29]

    Pyk2 is essential for a strocytes mobility following brain lesion: Pyk2 in Astrogliosis

    Giralt A, Coura R, Girault JA. Pyk2 is essential for a strocytes mobility following brain lesion: Pyk2 in Astrogliosis. Glia. 2016 Apr;64(4):620–34

    work page 2016

  30. [30]

    Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice

    Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP. Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci. 2001 Mar;114(Pt 6):1179–87

    work page 2001

  31. [31]

    Calcineurin is essential for depolarization-induced nuclear translocation and tyrosine phosphorylation of PYK2 in neurons

    Faure C, Corvol JC, Toutant M, Valjent E, Hvalby Ø, Jensen V, et al. Calcineurin is essential for depolarization-induced nuclear translocation and tyrosine phosphorylation of PYK2 in neurons. Journal of Cell Science. 2007 Sep 1;120(17):3034–44

    work page 2007

  32. [32]

    Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

    Faure C, Ramos M, Girault JA. Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation. Cell Mol Life Sci. 2013 Jan;70(1):137–52

    work page 2013

  33. [33]

    Lifeact: a versatile marker to visualize F-actin

    Riedl J, Crevenna AH, Kessenbrock K, Yu JH, Neukirchen D, Bista M, et al. Lifeact: a versatile marker to visualize F-actin. Nat Methods. 2008 Jul;5(7):605–7

    work page 2008

  34. [34]

    Systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector

    Liu Z, Chen O, Wall JBJ, Zheng M, Zhou Y, Wang L, et al. Systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector. Sci Rep. 2017 May 19;7(1):2193

    work page 2017

  35. [35]

    Activity -Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

    Frandemiche ML, De Seranno S, Rush T, Borel E, Elie A, Arnal I, et al. Activity -Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers. Journal of Neuroscience. 2014 Apr 23;34(17):6084–97

    work page 2014

  36. [36]

    Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylation -dependent mechanism

    Ramirez-Rios S, Denarier E, Prezel E, Vinit A, Stoppin -Mellet V, Devred F, et al. Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylation -dependent mechanism. Mol Biol Cell. 2016 Oct 1;27(19):2924–34

    work page 2016

  37. [37]

    In vitro characterization of conditions for amyloid - beta peptide oligomerization and fibrillogenesis

    Stine WB, Dahlgren KN, Krafft GA, LaDu MJ. In vitro characterization of conditions for amyloid - beta peptide oligomerization and fibrillogenesis. J Biol Chem. 2003 Mar 28;278(13):11612–22

    work page 2003

  38. [38]

    TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide

    Bosson A, Paumier A, Boisseau S, Jacquier -Sarlin M, Buisson A, Albrieux M. TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide. Mol Neurodegeneration. 2017 Dec;12(1):53

    work page 2017

  39. [39]

    A vicious cycle of β amyloid-dependent neuronal hyperactivation

    Zott B, Simon MM, Hong W, Unger F, Chen -Engerer HJ, Frosc h MP, et al. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science. 2019 Aug 9;365(6453):559–65

    work page 2019

  40. [40]

    Aβ Oligomers Dysregulate Calcium Homeostasis by Mechanosensitive Activation of AMPA and NMDA Receptors

    Fani G, Mannini B, Vecchi G, Cascella R, Cecchi C, Dobson CM, et al. Aβ Oligomers Dysregulate Calcium Homeostasis by Mechanosensitive Activation of AMPA and NMDA Receptors. ACS Chem Neurosci. 2021 Feb 17;12(4):766–81

    work page 2021

  41. [41]

    Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions

    Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, et al. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature. 1995 Aug 31;376(6543):737–45

    work page 1995

  42. [42]

    Interactions between two cytoskeleton -associated tyrosine kinases: calcium -dependent tyrosine kinase and focal adhesion tyrosine kinase

    Li X, Dy RC, Cance WG, Graves LM, Ea rp HS. Interactions between two cytoskeleton -associated tyrosine kinases: calcium -dependent tyrosine kinase and focal adhesion tyrosine kinase. J Biol Chem. 1999 Mar 26;274(13):8917–24

    work page 1999

  43. [43]

    RAFTK/Pyk2 Activation Is Mediated by Trans -acting Autophosphorylation in a Src -independent Manner

    Park SY, Avraham HK, Avraham S. RAFTK/Pyk2 Activation Is Mediated by Trans -acting Autophosphorylation in a Src -independent Manner. Journal of Biological Chemistry. 2004 Aug;279(32):33315–22. 44

    work page 2004

  44. [44]

    Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer’s Disease Mouse Models

    Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, Van Eersel J, et al. Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer’s Disease Mouse Models. Cell. 2010 Aug;142(3):387–97

    work page 2010

  45. [45]

    NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

    Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia. 2018 Apr;14(4):535–62

    work page 2018

  46. [46]

    The GSK3 hypothesis of Alzheimer’s disease

    Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s disease. J Neurochem. 2008 Mar;104(6):1433–9

    work page 2008

  47. [47]

    Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model

    Giralt A, Brito V, Chevy Q, Simonnet C, Otsu Y, Cifuentes-Díaz C, et al. Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model. Nat Commun. 2017 May 30;8(1):15592

    work page 2017

  48. [48]

    Protein-tyrosine kinase CAKβ/PYK2 is activated by binding Ca2+/calmodulin to FERM F2 α2 helix and thus forming its dimer

    Kohno T, Matsuda E, Sasaki H, Sasaki T. Protein-tyrosine kinase CAKβ/PYK2 is activated by binding Ca2+/calmodulin to FERM F2 α2 helix and thus forming its dimer. Biochemical Journal. 2008 Mar 15;410(3):513–23

    work page 2008

  49. [49]

    Synapse loss in frontal cortex biopsies in Alzheimer’s disease: Correlation with cognitive severity

    DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: Correlation with cognitive severity. Ann Neurol. 1990 May;27(5):457–64

    work page 1990

  50. [50]

    Physical basis of cognitive alterations in alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment

    Terry RD, M asliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4):572–80

    work page 1991

  51. [51]

    Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment

    Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology. 2007 May 1;68(18):1501–8

    work page 2007

  52. [52]

    Meta -analysis of synaptic pathology in Alzheimer’s disease reveals selective molecular vesicular machinery vulnerability

    de Wilde MC, Overk CR, Sijben JW, Masliah E. Meta -analysis of synaptic pathology in Alzheimer’s disease reveals selective molecular vesicular machinery vulnerability. Alzheimers Dement. 2016 Jun;12(6):633–44

    work page 2016

  53. [53]

    Synaptic density and cognitive performance in Alzheimer’s disease: A PET imagi ng study with [ 11 C]UCB-J

    Mecca AP, O’Dell RS, Sharp ES, Banks ER, Bartlett HH, Zhao W, et al. Synaptic density and cognitive performance in Alzheimer’s disease: A PET imagi ng study with [ 11 C]UCB-J. Alzheimer’s & Dementia. 2022 Dec;18(12):2527–36

    work page 2022

  54. [54]

    SH2 - and SH3 -mediated Interactions between Focal Adhesion Kinase and Src

    Thomas JW, Ellis B, Boerner RJ, Knight WB, White GC, Schaller MD. SH2 - and SH3 -mediated Interactions between Focal Adhesion Kinase and Src. Journal of Biological Chemistry. 1998 Jan;273(1):577–83

    work page 1998

  55. [55]

    Tau interacts with src-family non-receptor tyrosine kinases

    Lee G, Newman ST, Gard DL, Band H, Panchamoorthy G. Tau interacts with src-family non-receptor tyrosine kinases. J Cell Sci. 1998 Nov;111 ( Pt 21):3167–77

    work page 1998

  56. [56]

    Pyk2 suppresses contextual fear memory in an autophosphorylation-independent manner

    Zheng J, Suo L, Zhou Y, Jia L, Li J, Kuang Y, et al. Pyk2 suppresses contextual fear memory in an autophosphorylation-independent manner. J Mol Cell Biol. 2022 Jan 21;13(11):808–21

    work page 2022

  57. [57]

    Conformational Dynamics of FERM -Mediated Autoinhibition in Pyk2 Tyrosine Kinase

    Loving HS, Underbakke ES. Conformational Dynamics of FERM -Mediated Autoinhibition in Pyk2 Tyrosine Kinase. Biochemistry. 2019 Sep 10;58(36):3767–76

    work page 2019

  58. [58]

    PYK2 senses calcium through a disordered dimerization and calmodulin-binding element

    Momin AA, Mendes T, Barthe P, Faure C, Hong S, Yu P, et al. PYK2 senses calcium through a disordered dimerization and calmodulin-binding element. Commun Biol. 2022 Aug 9;5(1):800. 45

    work page 2022

  59. [59]

    GSK -3 Is Activated by the Tyrosine Kinase Pyk2 during LPA 1 -mediated Neurite Retraction

    Sayas CL, Ariaens A, Ponsioen B, Moolenaar WH. GSK -3 Is Activated by the Tyrosine Kinase Pyk2 during LPA 1 -mediated Neurite Retraction. MBoC. 2006 Apr;17(4):1834–44

    work page 2006

  60. [60]

    Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease

    Taddei RN, Perbet R, Mate De Gerando A, Wiedmer AE, Sanchez-Mico M, Connors Stewart T, et al. Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease. JAMA Neurol. 2023 Nov 1;80(11):1209. Additional file Additional file 1.docx Supplementary Figure 1: Control experiments showing the specificity of the Pyk2 –Tau interact...

    work page 2023