Synaptic Loss, ER Stress and Neuro-Inflammation Emerge Late in the Lateral Temporal Cortex and Associate with Progressive Tau Pathology in Alzheimer's Disease.
Aged
Aged, 80 and over
Alzheimer Disease
/ metabolism
Amyloid beta-Peptides
/ metabolism
Biomarkers
/ metabolism
Brain
/ metabolism
Cognition
/ physiology
Cognitive Dysfunction
/ metabolism
Endoplasmic Reticulum Stress
/ physiology
Female
Humans
Inflammation
/ pathology
Male
tau Proteins
/ metabolism
Alzheimer’s disease
Amyloid-β
Neuro-inflammation
Synapse
Tau
Unfolded protein response
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Aug 2020
Aug 2020
Historique:
received:
24
02
2020
accepted:
22
05
2020
pubmed:
10
6
2020
medline:
8
6
2021
entrez:
10
6
2020
Statut:
ppublish
Résumé
The complex multifactorial nature of AD pathogenesis has been highlighted by evidence implicating additional neurodegenerative mechanisms, beyond that of amyloid-β (Aβ) and tau. To provide insight into cause and effect, we here investigated the temporal profile and associations of pathological changes in synaptic, endoplasmic reticulum (ER) stress and neuro-inflammatory markers. Quantifications were established via immunoblot and immunohistochemistry protocols in post-mortem lateral temporal cortex (n = 46). All measures were assessed according to diagnosis (non-AD vs. AD), neuropathological severity (low (Braak ≤ 2) vs. moderate (3-4) vs. severe (≥ 5)) and individual Braak stage, and were correlated with Aβ and tau pathology and cognitive scores. Postsynaptic PSD-95, but not presynaptic synaptophysin, was decreased in AD cases and demonstrated a progressive decline across disease severity and Braak stage, yet not with cognitive scores. Of all investigated ER stress markers, only phospho-protein kinase RNA-like ER kinase (p-PERK) correlated with Braak stage and was increased in diagnosed AD cases. A similar relationship was observed for the astrocytic glial fibrillary acidic protein (GFAP); however, the associated aquaporin 4 and microglial Iba1 remained unchanged. Pathological alterations in these markers preferentially correlated with measures of tau over those related to Aβ. Notably, GFAP also correlated strongly with Aβ markers and with all assessments of cognition. Lateral temporal cortex-associated synaptic, ER stress and neuro-inflammatory pathologies are here determined as late occurrences in AD progression, largely associated with tau pathology. Moreover, GFAP emerged as the most robust indicator of disease progression, tau/Aβ pathology, and cognitive impairment.
Identifiants
pubmed: 32514860
doi: 10.1007/s12035-020-01950-1
pii: 10.1007/s12035-020-01950-1
pmc: PMC7340653
doi:
Substances chimiques
Amyloid beta-Peptides
0
Biomarkers
0
tau Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3258-3272Subventions
Organisme : Alzheimer's Research UK
ID : PPG2014A-21
Organisme : Alzheimer's Research UK
ID : ARUK-NCG2017A-3
Organisme : Alzheimer's Research Trust
ID : ARUK-NSG2015-1
Organisme : Alzheimer's Society
ID : 228
Pays : United Kingdom
Références
Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185. https://doi.org/10.1126/science.1566067
doi: 10.1126/science.1566067
pubmed: 1566067
Koss DJ, Jones G, Cranston A, Gardner H, Kanaan NM, Platt B (2016) Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline. Acta Neuropathol 132(6):875–895. https://doi.org/10.1007/s00401-016-1632-3
doi: 10.1007/s00401-016-1632-3
pubmed: 27770234
pmcid: 5106509
Koss DJ, Dubini M, Buchanan H, Hull C, Platt B (2018) Distinctive temporal profiles of detergent-soluble and -insoluble tau and Aβ species in human Alzheimer’s disease. Brain Res 1699:121–134. https://doi.org/10.1016/j.brainres.2018.08.014
doi: 10.1016/j.brainres.2018.08.014
pubmed: 30102892
Yang T, Li S, Xu H, Walsh DM, Selkoe DJ (2017) Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. J Neurosci 37(1):152–163. https://doi.org/10.1523/jneurosci.1698-16.2016
doi: 10.1523/jneurosci.1698-16.2016
pubmed: 28053038
pmcid: 5214627
Cummings JL, Morstorf T, Zhong K (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 6(4):37. https://doi.org/10.1186/alzrt269
doi: 10.1186/alzrt269
pubmed: 25024750
pmcid: 4095696
Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16(3):271–278; discussion 278-284. https://doi.org/10.1016/0197-4580(95)00021-6
doi: 10.1016/0197-4580(95)00021-6
pubmed: 7566337
Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58(12):1791–1800. https://doi.org/10.1212/wnl.58.12.1791
doi: 10.1212/wnl.58.12.1791
pubmed: 12084879
Grothe MJ, Barthel H, Sepulcre J, Dyrba M, Sabri O, Teipel SJ (2017) In vivo staging of regional amyloid deposition. Neurology 89(20):2031–2038. https://doi.org/10.1212/wnl.0000000000004643
doi: 10.1212/wnl.0000000000004643
pubmed: 29046362
pmcid: 5711511
Cho H, Lee HS, Choi JY, Lee JH, Ryu YH, Lee MS, Lyoo CH (2018) Predicted sequence of cortical tau and amyloid-β deposition in Alzheimer disease spectrum. Neurobiol Aging 68:76–84. https://doi.org/10.1016/j.neurobiolaging.2018.04.007
doi: 10.1016/j.neurobiolaging.2018.04.007
pubmed: 29751288
Giannakopoulos P, Herrmann FR, Bussière T, Bouras C, Kövari E, Perl DP, Morrison JH, Gold G et al (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60(9):1495–1500. https://doi.org/10.1212/01.wnl.0000063311.58879.01
doi: 10.1212/01.wnl.0000063311.58879.01
pubmed: 12743238
Mullane K, Williams M (2018) Alzheimer’s disease (AD) therapeutics - 1: repeated clinical failures continue to question the amyloid hypothesis of AD and the current understanding of AD causality. Biochem Pharmacol 158:359–375. https://doi.org/10.1016/j.bcp.2018.09.026
doi: 10.1016/j.bcp.2018.09.026
pubmed: 30273553
Cubinkova V, Valachova B, Uhrinova I, Brezovakova V, Smolek T, Jadhav S, Zilka N (2018) Alternative hypotheses related to Alzheimer’s disease. Bratisl Lek Listy 119(4):210–216. https://doi.org/10.4149/bll_2018_039
doi: 10.4149/bll_2018_039
pubmed: 29663818
Overk CR, Masliah E (2014) Pathogenesis of synaptic degeneration in Alzheimer’s disease and Lewy body disease. Biochem Pharmacol 88(4):508–516. https://doi.org/10.1016/j.bcp.2014.01.015
doi: 10.1016/j.bcp.2014.01.015
pubmed: 24462903
pmcid: 3973539
Koss DJ, Platt B (2017) Alzheimer’s disease pathology and the unfolded protein response: prospective pathways and therapeutic targets. Behav Pharmacol 28(2 and 3-Spec Issue):161–178. https://doi.org/10.1097/fbp.0000000000000299
doi: 10.1097/fbp.0000000000000299
pubmed: 28252521
Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16(6):358–372. https://doi.org/10.1038/nrn3880
doi: 10.1038/nrn3880
pubmed: 25991443
de Wilde MC, Overk CR, Sijben JW, Masliah E (2016) Meta-analysis of synaptic pathology in Alzheimer’s disease reveals selective molecular vesicular machinery vulnerability. Alzheimers Dement 12(6):633–644. https://doi.org/10.1016/j.jalz.2015.12.005
doi: 10.1016/j.jalz.2015.12.005
pubmed: 26776762
pmcid: 5058345
DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27(5):457–464. https://doi.org/10.1002/ana.410270502
doi: 10.1002/ana.410270502
pubmed: 2360787
Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27(10):1372–1384. https://doi.org/10.1016/j.neurobiolaging.2005.09.012
doi: 10.1016/j.neurobiolaging.2005.09.012
pubmed: 16289476
Masliah E, Mallory M, Hansen L, DeTeresa R, Alford M, Terry R (1994) Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci Lett 174(1):67–72. https://doi.org/10.1016/0304-3940(94)90121-x
doi: 10.1016/0304-3940(94)90121-x
pubmed: 7970158
Chang RC, Wong AK, Ng HK, Hugon J (2002) Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer’s disease. Neuroreport 13(18):2429–2432. https://doi.org/10.1097/00001756-200212200-00011
doi: 10.1097/00001756-200212200-00011
pubmed: 12499843
Duran-Aniotz C, Cornejo VH, Espinoza S, Ardiles ÁO, Medinas DB, Salazar C, Foley A, Gajardo I et al (2017) IRE1 signaling exacerbates Alzheimer’s disease pathogenesis. Acta Neuropathol 134(3):489–506. https://doi.org/10.1007/s00401-017-1694-x
doi: 10.1007/s00401-017-1694-x
pubmed: 28341998
Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, Lee VM, Trojanowski JQ, Devlin B et al (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun 1:31. https://doi.org/10.1186/2051-5960-1-31
doi: 10.1186/2051-5960-1-31
pubmed: 24252572
pmcid: 3893579
Radford H, Moreno JA, Verity N, Halliday M, Mallucci GR (2015) PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol 130(5):633–642. https://doi.org/10.1007/s00401-015-1487-z
doi: 10.1007/s00401-015-1487-z
pubmed: 26450683
pmcid: 4612323
Abisambra JF, Jinwal UK, Blair LJ, O'Leary JC 3rd, Li Q, Brady S, Wang L, Guidi CE et al (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33(22):9498–9507. https://doi.org/10.1523/jneurosci.5397-12.2013
doi: 10.1523/jneurosci.5397-12.2013
pubmed: 23719816
pmcid: 3733249
Devi L, Ohno M (2014) PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer’s disease. Neurobiol Aging 35(10):2272–2281. https://doi.org/10.1016/j.neurobiolaging.2014.04.031
doi: 10.1016/j.neurobiolaging.2014.04.031
pubmed: 24889041
pmcid: 4127890
Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 174(4):1241–1251. https://doi.org/10.2353/ajpath.2009.080814
doi: 10.2353/ajpath.2009.080814
pubmed: 19264902
pmcid: 2671357
Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ (2012) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol 226(5):693–702. https://doi.org/10.1002/path.3969
doi: 10.1002/path.3969
pubmed: 22102449
Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, Smith E, Ortori CA et al (2017) Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain J Neurol 140(6):1768–1783. https://doi.org/10.1093/brain/awx074
doi: 10.1093/brain/awx074
Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E (2013) Suppression of eIF2α kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci 16(9):1299–1305. https://doi.org/10.1038/nn.3486
doi: 10.1038/nn.3486
pubmed: 23933749
pmcid: 3756900
Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA (2012) Neuroinflammation and synaptic loss. Neurochem Res 37(5):903–910. https://doi.org/10.1007/s11064-012-0708-2
doi: 10.1007/s11064-012-0708-2
pubmed: 22311128
pmcid: 3478877
Santos LE, Ferreira ST (2018) Crosstalk between endoplasmic reticulum stress and brain inflammation in Alzheimer’s disease. Neuropharmacology 136(Pt B):350–360. https://doi.org/10.1016/j.neuropharm.2017.11.016
doi: 10.1016/j.neuropharm.2017.11.016
pubmed: 29129774
Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, Rosenkrantz LL, Imboywa S et al (2013) CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16(7):848–850. https://doi.org/10.1038/nn.3435
doi: 10.1038/nn.3435
pubmed: 23708142
pmcid: 3703870
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2):107–116. https://doi.org/10.1056/NEJMoa1211103
doi: 10.1056/NEJMoa1211103
pubmed: 23150908
Gylys KH, Fein JA, Yang F, Wiley DJ, Miller CA, Cole GM (2004) Synaptic changes in Alzheimer’s disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol 165(5):1809–1817. https://doi.org/10.1016/s0002-9440(10)63436-0
doi: 10.1016/s0002-9440(10)63436-0
pubmed: 15509549
pmcid: 1618663
Janota CS, Brites D, Lemere CA, Brito MA (2015) Glio-vascular changes during ageing in wild-type and Alzheimer’s disease-like APP/PS1 mice. Brain Res 1620:153–168. https://doi.org/10.1016/j.brainres.2015.04.056
doi: 10.1016/j.brainres.2015.04.056
pubmed: 25966615
pmcid: 4549169
Yang C, Huang X, Huang X, Mai H, Li J, Jiang T, Wang X, Lü T (2016) Aquaporin-4 and Alzheimer’s disease. J Alzheimers Dis 52(2):391–402. https://doi.org/10.3233/jad-150949
doi: 10.3233/jad-150949
pubmed: 27031475
Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, Morris JC (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56(1):127–129. https://doi.org/10.1212/wnl.56.1.127
doi: 10.1212/wnl.56.1.127
pubmed: 11148253
Carter SF, Schöll M, Almkvist O, Wall A, Engler H, Långström B, Nordberg A (2012) Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53(1):37–46. https://doi.org/10.2967/jnumed.110.087031
doi: 10.2967/jnumed.110.087031
pubmed: 22213821
Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J et al (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128(6):755–766. https://doi.org/10.1007/s00401-014-1349-0
doi: 10.1007/s00401-014-1349-0
pubmed: 25348064
pmcid: 4257842
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C et al (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8(1):1–13. https://doi.org/10.1016/j.jalz.2011.10.007
doi: 10.1016/j.jalz.2011.10.007
pubmed: 22265587
pmcid: 3266529
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580. https://doi.org/10.1002/ana.410300410
doi: 10.1002/ana.410300410
pubmed: 1789684
Pham E, Crews L, Ubhi K, Hansen L, Adame A, Cartier A, Salmon D, Galasko D et al (2010) Progressive accumulation of amyloid-beta oligomers in Alzheimer’s disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins. FEBS J 277(14):3051–3067. https://doi.org/10.1111/j.1742-4658.2010.07719.x
doi: 10.1111/j.1742-4658.2010.07719.x
pubmed: 20573181
pmcid: 2933033
Shinohara M, Fujioka S, Murray ME, Wojtas A, Baker M, Rovelet-Lecrux A, Rademakers R, Das P et al (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease. Brain J Neurol 137(Pt 5):1533–1549. https://doi.org/10.1093/brain/awu046
doi: 10.1093/brain/awu046
Counts SE, Nadeem M, Lad SP, Wuu J, Mufson EJ (2006) Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. J Neuropathol Exp Neurol 65(6):592–601. https://doi.org/10.1097/00005072-200606000-00007
doi: 10.1097/00005072-200606000-00007
pubmed: 16783169
Love S, Siew LK, Dawbarn D, Wilcock GK, Ben-Shlomo Y, Allen SJ (2006) Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol Aging 27(6):797–803. https://doi.org/10.1016/j.neurobiolaging.2005.04.008
doi: 10.1016/j.neurobiolaging.2005.04.008
pubmed: 15979210
Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56(8):933–944. https://doi.org/10.1097/00005072-199708000-00011
doi: 10.1097/00005072-199708000-00011
pubmed: 9258263
Reddy PH, Mani G, Park BS, Jacques J, Murdoch G, Whetsell W Jr, Kaye J, Manczak M (2005) Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J Alzheimers Dis 7(2):103–117; discussion 173-180. https://doi.org/10.3233/jad-2005-7203
doi: 10.3233/jad-2005-7203
pubmed: 15851848
Bereczki E, Francis PT, Howlett D, Pereira JB, Höglund K, Bogstedt A, Cedazo-Minguez A, Baek JH et al (2016) Synaptic proteins predict cognitive decline in Alzheimer’s disease and Lewy body dementia. Alzheimers Dement 12(11):1149–1158. https://doi.org/10.1016/j.jalz.2016.04.005
doi: 10.1016/j.jalz.2016.04.005
pubmed: 27224930
Scheff SW, Price DA (2006) Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimers Dis 9(3 Suppl):101–115. https://doi.org/10.3233/jad-2006-9s312
doi: 10.3233/jad-2006-9s312
pubmed: 16914849
Hatanpää K, Isaacs KR, Shirao T, Brady DR, Rapoport SI (1999) Loss of proteins regulating synaptic plasticity in normal aging of the human brain and in Alzheimer disease. J Neuropathol Exp Neurol 58(6):637–643. https://doi.org/10.1097/00005072-199906000-00008
doi: 10.1097/00005072-199906000-00008
pubmed: 10374754
Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, Gertz HJ, Xuereb JH, Hills R, Brayne C, Huppert FA et al (2000) Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol 157(2):623–636. https://doi.org/10.1016/s0002-9440(10)64573-7
doi: 10.1016/s0002-9440(10)64573-7
pubmed: 10934165
pmcid: 1850134
Bossers K, Wirz KT, Meerhoff GF, Essing AH, van Dongen JW, Houba P, Kruse CG, Verhaagen J et al (2010) Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain J Neurol 133(Pt 12):3699–3723. https://doi.org/10.1093/brain/awq258
doi: 10.1093/brain/awq258
Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A 101(1):343–347. https://doi.org/10.1073/pnas.2634794100
doi: 10.1073/pnas.2634794100
pubmed: 14660786
Leuba G, Walzer C, Vernay A, Carnal B, Kraftsik R, Piotton F, Marin P, Bouras C et al (2008) Postsynaptic density protein PSD-95 expression in Alzheimer’s disease and okadaic acid induced neuritic retraction. Neurobiol Dis 30(3):408–419. https://doi.org/10.1016/j.nbd.2008.02.012
doi: 10.1016/j.nbd.2008.02.012
pubmed: 18424056
Scheff SW, DeKosky ST, Price DA (1990) Quantitative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol Aging 11(1):29–37. https://doi.org/10.1016/0197-4580(90)90059-9
doi: 10.1016/0197-4580(90)90059-9
pubmed: 2325814
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842. https://doi.org/10.1038/nm1782
doi: 10.1038/nm1782
pubmed: 18568035
pmcid: 2772133
Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ et al (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A 106(10):4012–4017. https://doi.org/10.1073/pnas.0811698106
doi: 10.1073/pnas.0811698106
pubmed: 19228947
pmcid: 2656196
Liu J, Chang L, Roselli F, Almeida OF, Gao X, Wang X, Yew DT, Wu Y (2010) Amyloid-β induces caspase-dependent loss of PSD-95 and synaptophysin through NMDA receptors. J Alzheimers Dis 22(2):541–556. https://doi.org/10.3233/jad-2010-100948
doi: 10.3233/jad-2010-100948
pubmed: 20847396
Schindowski K, Bretteville A, Leroy K, Bégard S, Brion JP, Hamdane M, Buée L (2006) Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169(2):599–616. https://doi.org/10.2353/ajpath.2006.060002
doi: 10.2353/ajpath.2006.060002
pubmed: 16877359
pmcid: 1698785
Koss DJ, Robinson L, Drever BD, Plucińska K, Stoppelkamp S, Veselcic P, Riedel G, Platt B (2016) Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology. Neurobiol Dis 91:105–123. https://doi.org/10.1016/j.nbd.2016.03.002
doi: 10.1016/j.nbd.2016.03.002
pubmed: 26949217
Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, Dawson HN, Vitek MP et al (2011) Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci 31(5):1688–1692. https://doi.org/10.1523/jneurosci.2610-10.2011
doi: 10.1523/jneurosci.2610-10.2011
pubmed: 21289177
pmcid: 3836238
Miller EC, Teravskis PJ, Dummer BW, Zhao X, Huganir RL, Liao D (2014) Tau phosphorylation and tau mislocalization mediate soluble Aβ oligomer-induced AMPA glutamate receptor signaling deficits. Eur J Neurosci 39(7):1214–1224. https://doi.org/10.1111/ejn.12507
doi: 10.1111/ejn.12507
pubmed: 24713000
pmcid: 4123852
Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J et al (2012) Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485(7399):507–511. https://doi.org/10.1038/nature11058
doi: 10.1038/nature11058
pubmed: 22622579
pmcid: 3378208
de la Monte SM, Re E, Longato L, Tong M (2012) Dysfunctional pro-ceramide, ER stress, and insulin/IGF signaling networks with progression of Alzheimer’s disease. J Alzheimers Dis 30(Suppl 2 (0 2)):S217–S229. https://doi.org/10.3233/jad-2012-111728
doi: 10.3233/jad-2012-111728
pubmed: 22297646
pmcid: 4562691
Baek JH, Whitfield D, Howlett D, Francis P, Bereczki E, Ballard C, Hortobágyi T, Attems J et al (2016) Unfolded protein response is activated in Lewy body dementias. Neuropathol Appl Neurobiol 42(4):352–365. https://doi.org/10.1111/nan.12260
doi: 10.1111/nan.12260
pubmed: 26202523
Alberdi E, Wyssenbach A, Alberdi M, Sánchez-Gómez MV, Cavaliere F, Rodríguez JJ, Verkhratsky A, Matute C (2013) Ca(2+) -dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer’s disease. Aging Cell 12(2):292–302. https://doi.org/10.1111/acel.12054
doi: 10.1111/acel.12054
pubmed: 23409977
Botteri G, Salvadó L, Gumà A, Lee Hamilton D, Meakin PJ, Montagut G, Ashford MLJ, Ceperuelo-Mallafré V et al (2018) The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling. Metab Clin Exp 85:59–75. https://doi.org/10.1016/j.metabol.2018.03.005
doi: 10.1016/j.metabol.2018.03.005
pubmed: 29526536
O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B et al (2008) Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron 60(6):988–1009. https://doi.org/10.1016/j.neuron.2008.10.047
doi: 10.1016/j.neuron.2008.10.047
pubmed: 19109907
pmcid: 2667382
Ferrer I, Santpere G, Arzberger T, Bell J, Blanco R, Boluda S, Budka H, Carmona M et al (2007) Brain protein preservation largely depends on the postmortem storage temperature: implications for study of proteins in human neurologic diseases and management of brain banks: a BrainNet Europe study. J Neuropathol Exp Neurol 66(1):35–46. https://doi.org/10.1097/nen.0b013e31802c3e7d
doi: 10.1097/nen.0b013e31802c3e7d
pubmed: 17204935
Wang Y, Zhang Y, Hu W, Xie S, Gong CX, Iqbal K, Liu F (2015) Rapid alteration of protein phosphorylation during postmortem: Implication in the study of protein phosphorylation. Sci Rep 5:15709. https://doi.org/10.1038/srep15709
doi: 10.1038/srep15709
pubmed: 26511732
pmcid: 4625177
Taipa R, Ferreira V, Brochado P, Robinson A, Reis I, Marques F, Mann DM, Melo-Pires M et al (2018) Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: a post mortem study. Neuropathol Appl Neurobiol 44(3):298–313. https://doi.org/10.1111/nan.12445
doi: 10.1111/nan.12445
pubmed: 29044639
Choo IL, Carter SF, Schöll ML, Nordberg A (2014) Astrocytosis measured by
doi: 10.1007/s00259-014-2859-7
pubmed: 25077930
Rodriguez-Vieitez E, Ni R, Gulyás B, Tóth M, Häggkvist J, Halldin C, Voytenko L, Marutle A et al (2015) Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol Imaging 42(7):1119–1132. https://doi.org/10.1007/s00259-015-3047-0
doi: 10.1007/s00259-015-3047-0
pubmed: 25893384
pmcid: 4424277
Cuello AC (2017) Early and late CNS inflammation in Alzheimer’s disease: two extremes of a continuum? Trends Pharmacol Sci 38(11):956–966. https://doi.org/10.1016/j.tips.2017.07.005
doi: 10.1016/j.tips.2017.07.005
pubmed: 28867259
Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, Do Carmo S, Cuello AC (2014) Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer’s disease. Neurobiol Aging 35(10):2249–2262. https://doi.org/10.1016/j.neurobiolaging.2014.03.026
doi: 10.1016/j.neurobiolaging.2014.03.026
pubmed: 24831823
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F (2005) Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2:22. https://doi.org/10.1186/1742-2094-2-22
doi: 10.1186/1742-2094-2-22
pubmed: 16212664
pmcid: 1274341
Medeiros R, LaFerla FM (2013) Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol 239:133–138. https://doi.org/10.1016/j.expneurol.2012.10.007
doi: 10.1016/j.expneurol.2012.10.007
pubmed: 23063604
Serrano-Pozo A, Mielke ML, Gómez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT (2011) Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 179(3):1373–1384. https://doi.org/10.1016/j.ajpath.2011.05.047
doi: 10.1016/j.ajpath.2011.05.047
pubmed: 21777559
pmcid: 3157187
Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353(6301):777–783. https://doi.org/10.1126/science.aag2590
doi: 10.1126/science.aag2590
pubmed: 27540165
Santello M, Toni N, Volterra A (2019) Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci 22(2):154–166. https://doi.org/10.1038/s41593-018-0325-8
doi: 10.1038/s41593-018-0325-8
pubmed: 30664773
Reichenbach N, Delekate A, Breithausen B, Keppler K, Poll S, Schulte T, Peter J, Plescher M et al (2018) P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model. J Exp Med 215(6):1649–1663. https://doi.org/10.1084/jem.20171487
doi: 10.1084/jem.20171487
pubmed: 29724785
pmcid: 5987918
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4(147):147ra111. https://doi.org/10.1126/scitranslmed.3003748
doi: 10.1126/scitranslmed.3003748
pubmed: 22896675
pmcid: 3551275
Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, Cai Z, Wu T et al (2015) Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegener 10:58. https://doi.org/10.1186/s13024-015-0056-1
doi: 10.1186/s13024-015-0056-1
pubmed: 26526066
pmcid: 4631089
Smith AJ, Duan T, Verkman AS (2019) Aquaporin-4 reduces neuropathology in a mouse model of Alzheimer's disease by remodeling peri-plaque astrocyte structure. Acta Neuropathol Commun 7(1):74. https://doi.org/10.1186/s40478-019-0728-0
doi: 10.1186/s40478-019-0728-0
pubmed: 31068220
pmcid: 6506955
Hoshi A, Yamamoto T, Shimizu K, Ugawa Y, Nishizawa M, Takahashi H, Kakita A (2012) Characteristics of aquaporin expression surrounding senile plaques and cerebral amyloid angiopathy in Alzheimer disease. J Neuropathol Exp Neurol 71(8):750–759. https://doi.org/10.1097/NEN.0b013e3182632566
doi: 10.1097/NEN.0b013e3182632566
pubmed: 22805778
Hopperton KE, Mohammad D, Trépanier MO, Giuliano V, Bazinet RP (2018) Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review. Mol Psychiatry 23(2):177–198. https://doi.org/10.1038/mp.2017.246
doi: 10.1038/mp.2017.246
pubmed: 29230021
Serrano-Pozo A, Gómez-Isla T, Growdon JH, Frosch MP, Hyman BT (2013) A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 182(6):2332–2344. https://doi.org/10.1016/j.ajpath.2013.02.031
doi: 10.1016/j.ajpath.2013.02.031
pubmed: 23602650
pmcid: 3668030
Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70(4):532–540. https://doi.org/10.1002/ana.22615
doi: 10.1002/ana.22615
pubmed: 22028219
pmcid: 3203752