Patients with Alzheimer’s disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this ‘triggering’ function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ–tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.
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Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T. & Hyman, B. T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–639 (1992).
Ingelsson, M. et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62, 925–931 (2004).
Lleó, A., Berezovska, O., Growdon, J. H. & Hyman, B. T. Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am. J. Geriatr. Psychiatry 12, 146–156 (2004).
Ryan, N. S. et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 15, 1326–1335 (2016).
Hyman, B. T. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch. Neurol. 68, 1062–1064 (2011).
Choi, S. H. et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274–278 (2014).
Lee, H. K. et al. Three dimensional human neuro-spheroid model of Alzheimer’s disease based on differentiated induced pluripotent stem cells. PLoS One 11, e0163072 (2016).
Israel, M. A. et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220 (2012).
Oddo, S. et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409–421 (2003).
Maia, L. F. et al. Changes in amyloid-β and tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013).
Schelle, J. et al. Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimers Dement. 13, 701–709 (2017).
Bennett, R. E. et al. Enhanced tau aggregation in the presence of amyloid β. Am. J. Pathol. 187, 1601–1612 (2017).
Busche, M. A. et al. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat. Neurosci. 22, 57–64 (2019).
Villeneuve, S. et al. Existing Pittsburgh compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation. Brain 138, 2020–2033 (2015).
Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).
Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. J. Am. Med. Assoc. 313, 1924–1938 (2015).
Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766 (2014).
Jagust, W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci. 19, 687–700 (2018).
Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).
Jucker, M. & Walker, L. C. Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nat. Neurosci. 21, 1341–1349 (2018).
Peng, C., Trojanowski, J. Q. & Lee, V. M. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16, 199–212 (2020).
Pontecorvo, M. J. et al. Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain 140, 748–763 (2017).
Adams, J. N., Maass, A., Harrison, T. M., Baker, S. L. & Jagust, W. J. Cortical tau deposition follows patterns of entorhinal functional connectivity in aging. eLife 8, e49132 (2019).
Jacobs, H. I. L. et al. Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat. Neurosci. 21, 424–431 (2018).
Sperling, R. A. et al. The impact of amyloid-beta and tau on prospective cognitive decline in older individuals. Ann. Neurol. 85, 181–193 (2019).
Hanseeuw, B. J. et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 76, 915–924 (2019).
Timmers, M. et al. Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer’s disease. Neurobiol. Aging 79, 131–141 (2019).
Hanseeuw, B. J. et al. Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline. Ann. Neurol. 81, 583–596 (2017).
Pascoal, T. A. et al. Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol. Psychiatry 22, 306–311 (2017).
Wang, L. et al. Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy. JAMA Neurol. 73, 1070–1077 (2016).
Desikan, R. S. et al. Amyloid-β associated volume loss occurs only in the presence of phospho-tau. Ann. Neurol. 70, 657–661 (2011).
Fortea, J. et al. Cerebrospinal fluid β-amyloid and phospho-tau biomarker interactions affecting brain structure in preclinical Alzheimer disease. Ann. Neurol. 76, 223–230 (2014).
Takeda, S. et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat. Commun. 6, 8490 (2015).
Usenovic, M. et al. Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J. Neurosci. 35, 14234–14250 (2015).
Sepulcre, J. et al. Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nat. Med. 24, 1910–1918 (2018).
Ferrari, A., Hoerndli, F., Baechi, T., Nitsch, R. M. & Götz, J. beta-Amyloid induces paired helical filament-like tau filaments in tissue culture. J. Biol. Chem. 278, 40162–40168 (2003).
Götz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495 (2001).
Bolmont, T. et al. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am. J. Pathol. 171, 2012–2020 (2007).
Vergara, C. et al. Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo. Acta Neuropathol. 137, 397–412 (2019).
He, Z. et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018).
Leyns, C. E. G. et al. TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci. 22, 1217–1222 (2019).
Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).
Pooler, A. M. et al. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathol. Commun. 3, 14 (2015).
Gomes, L. A. et al. Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein. Acta Neuropathol. 138, 913–941 (2019).
Jackson, R. J. et al. Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer’s disease. Eur. J. Neurosci. 44, 3056–3066 (2016).
Ribé, E. M. et al. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol. Dis. 20, 814–822 (2005).
Chen, W. et al. Increased tauopathy drives microglia-mediated clearance of beta-amyloid. Acta Neuropathol. Commun. 4, 63 (2016).
Palop, J. J. & Mucke, L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17, 777–792 (2016).
Zott, B. et al. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science 365, 559–565 (2019).
Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007).
Roberson, E. D. et al. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J. Neurosci. 31, 700–711 (2011).
Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010).
Marinković, P. et al. In vivo imaging reveals reduced activity of neuronal circuits in a mouse tauopathy model. Brain 142, 1051–1062 (2019).
Menkes-Caspi, N. et al. Pathological tau disrupts ongoing network activity. Neuron 85, 959–966 (2015).
McInnes, J. et al. Synaptogyrin-3 mediates presynaptic dysfunction induced by tau. Neuron 97, 823–835.e8 (2018).
Hatch, R. J., Wei, Y., Xia, D. & Götz, J. Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. Acta Neuropathol. 133, 717–730 (2017).
Tracy, T. E. et al. Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90, 245–260 (2016).
Warmus, B. A. et al. Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia. J. Neurosci. 34, 16482–16495 (2014).
Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat. Neurosci. 22, 47–56 (2019).
Sierksma, A. et al. Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to tau pathology. EMBO Mol. Med. 12, e10606 (2020).
Pickett, E. K. et al. Amyloid beta and tau cooperate to cause reversible behavioral and transcriptional deficits in a model of Alzheimer’s disease. Cell Reports 29, 3592–3604.e5 (2019).
Ke, Y. D. et al. CNS cell type-specific gene profiling of P301S tau transgenic mice identifies genes dysregulated by progressive tau accumulation. J. Biol. Chem. 294, 14149–14162 (2019).
Evans, H. T., Benetatos, J., van Roijen, M., Bodea, L. G. & Götz, J. Decreased synthesis of ribosomal proteins in tauopathy revealed by non-canonical amino acid labelling. EMBO J. 38, e101174 (2019).
Kuchibhotla, K. V. et al. Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc. Natl. Acad. Sci. USA 111, 510–514 (2014).
Huijbers, W. et al. Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity. J. Neurosci. 39, 548–556 (2019).
Sohn, P. D. et al. Pathogenic tau impairs axon initial segment plasticity and excitability homeostasis. Neuron 104, 458–470.e5 (2019).
Das, M. et al. Neuronal levels and sequence of tau modulate the power of brain rhythms. Neurobiol. Dis. 117, 181–188 (2018).
DeVos, S. L. et al. Tau reduction in the presence of amyloid-β prevents tau pathology and neuronal death in vivo. Brain 141, 2194–2212 (2018).
Angulo, S. L. et al. Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit. Neurobiol. Dis. 108, 261–276 (2017).
Green, C. et al. Functional networks are impaired by elevated tau-protein but reversible in a regulatable Alzheimer’s disease mouse model. Mol. Neurodegener. 14, 13 (2019).
Schultz, A. P. et al. Phases of hyperconnectivity and hypoconnectivity in the default mode and salience networks track with amyloid and tau in clinically normal individuals. J. Neurosci. 37, 4323–4331 (2017).
Ondrejcak, T. et al. Soluble tau aggregates inhibit synaptic long-term depression and amyloid β-facilitated LTD in vivo. Neurobiol. Dis. 127, 582–590 (2019).
Chabrier, M. A., Cheng, D., Castello, N. A., Green, K. N. & LaFerla, F. M. Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease. Neurobiol. Dis. 64, 107–117 (2014).
Umeda, T. et al. Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice. Acta Neuropathol. 127, 685–698 (2014).
Vossel, K. A. et al. Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β. J. Cell Biol. 209, 419–433 (2015).
Ittner, L. M. et al. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proc. Natl. Acad. Sci. USA 105, 15997–16002 (2008).
Fang, E. F. et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412 (2019).
Manczak, M. & Reddy, P. H. Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum. Mol. Genet. 21, 5131–5146 (2012).
Pérez, M. J., Vergara-Pulgar, K., Jara, C., Cabezas-Opazo, F. & Quintanilla, R. A. Caspase-cleaved tau impairs mitochondrial dynamics in Alzheimer’s disease. Mol. Neurobiol. 55, 1004–1018 (2018).
Adalbert, R. et al. Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport. Neurobiol. Aging 68, 68–75 (2018).
Rhein, V. et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc. Natl. Acad. Sci. USA 106, 20057–20062 (2009).
Lippi, S. L. P., Smith, M. L. & Flinn, J. M. A novel hAPP/htau mouse model of Alzheimer’s disease: inclusion of APP with tau exacerbates behavioral deficits and zinc administration heightens tangle pathology. Front. Aging Neurosci. 10, 382 (2018).
Wang, C., Saar, V., Leung, K. L., Chen, L. & Wong, G. Human amyloid β peptide and tau co-expression impairs behavior and causes specific gene expression changes in Caenorhabditis elegans. Neurobiol. Dis. 109, 88–101 (2018). Pt A.
Benbow, S. J., Strovas, T. J., Darvas, M., Saxton, A. & Kraemer, B. C. Synergistic toxicity between tau and amyloid drives neuronal dysfunction and neurodegeneration in transgenic C. elegans. Hum. Mol. Genet. 29, 495–505 (2020).
Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Guerrero-Muoz, M. J., Jackson, G. R. & Kayed, R. Preparation and characterization of neurotoxic tau oligomers. Biochemistry 49, 10039–10041 (2010).
Vasconcelos, B. et al. Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. Acta Neuropathol. 131, 549–569 (2016).
Griner, S. L. et al. Structure-based inhibitors of amyloid beta core suggest a common interface with tau. eLife 8, e46924 (2019).
Ittner, A. et al. Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice. Science 354, 904–908 (2016).
Manczak, M. & Reddy, P. H. Abnormal interaction of oligomeric amyloid-β with phosphorylated tau: implications to synaptic dysfunction and neuronal damage. J. Alzheimers Dis. 36, 285–295 (2013).
Perez-Nievas, B. G. et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain 136, 2510–2526 (2013).
Prinz, M., Jung, S. & Priller, J. Microglia biology: one century of evolving concepts. Cell 179, 292–311 (2019).
Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).
Maphis, N. et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138, 1738–1755 (2015).
Mancuso, R. et al. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain 142, 3243–3264 (2019).
Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).
Bolós, M. et al. Direct evidence of internalization of tau by microglia in vitro and in vivo. J. Alzheimers Dis. 50, 77–87 (2016).
Hopp, S. C. et al. The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease. J. Neuroinflammation 15, 269 (2018).
Cserép, C. et al. Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science 367, 528–537 (2020).
Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).
Shi, Y. et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216, 2546–2561 (2019).
Dejanovic, B. et al. Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron 100, 1322–1336.e7 (2018).
Martini-Stoica, H. et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J. Exp. Med. 215, 2355–2377 (2018).
de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697 (2012).
Tai, X. Y. et al. Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections. Brain 139, 2441–2455 (2016).
Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat. Neurosci. 19, 1085–1092 (2016).
Schultz, M. K. Jr. et al. Pharmacogenetic neuronal stimulation increases human tau pathology and trans-synaptic spread of tau to distal brain regions in mice. Neurobiol. Dis. 118, 161–176 (2018).
Rodriguez, G.A., Barrett, G.M., Duff, K.E. & Hussaini, S.A. Attenuation of entorhinal cortex hyperactivity reduces Aβ and tau pathology. Preprint at bioRxiv https://doi.org/10.1101/487405 (2019).
Yap, E. L. & Greenberg, M. E. Activity-regulated transcription: bridging the gap between neural activity and behavior. Neuron 100, 330–348 (2018).
Bezprozvanny, I. & Mattson, M. P. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci. 31, 454–463 (2008).
Therriault, J. et al. APOEε4 potentiates the relationship between amyloid-β and tau pathologies. Mol. Psychiatry https://doi.org/10.1038/s41380-020-0688-6 (2020).
Kounnas, M. Z. et al. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell 82, 331–340 (1995).
Rauch, J. N. et al. LRP1 is a master regulator of tau uptake and spread. Nature 580, 381–385 (2020).
Bassil, F. et al. Amyloid-Beta (Aβ) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of lewy body disorders with Aβ pathology. Neuron 105, 260–275.e6 (2020).
Guo, J. L. et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103–117 (2013).
Corbett, G. T. et al. PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins. Acta Neuropathol. 139, 503–526 (2020).
Zhang, F. et al. β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aay6931 (2020).
Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019).
Senatorov, V.V. Jr. et al. Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaw8283 (2019).
Milikovsky, D.Z. et al. Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaw8954 (2019).
Sun, W., Samimi, H., Gamez, M., Zare, H. & Frost, B. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat. Neurosci. 21, 1038–1048 (2018).
Eftekharzadeh, B. et al. Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99, 925–940.e7 (2018).
Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H. & LaFerla, F. M. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332 (2004).
Rasool, S., Martinez-Coria, H., Wu, J. W., LaFerla, F. & Glabe, C. G. Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Aβ deposition and tau pathology in 3xTg-AD mice. J. Neurochem. 126, 473–482 (2013).
Rosenberg, R. N., Fu, M. & Lambracht-Washington, D. Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology. Alzheimers Res. Ther. 10, 115 (2018).
Saito, T. et al. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. J. Biol. Chem. 294, 12754–12765 (2019).
Gamache, J. et al. Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice. Nat. Commun. 10, 2479 (2019).
Iturria-Medina, Y., Sotero, R. C., Toussaint, P. J., Mateos-Pérez, J. M. & Evans, A. C. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016).
Wang, X. et al. Cerebrovascular hypoperfusion induces spatial memory impairment, synaptic changes, and amyloid-β oligomerization in rats. J. Alzheimers Dis. 21, 813–822 (2010).
Kitaguchi, H. et al. Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice. Brain Res. 1294, 202–210 (2009).
Qiu, L. et al. Chronic cerebral hypoperfusion enhances tau hyperphosphorylation and reduces autophagy in Alzheimer’s disease mice. Sci. Rep. 6, 23964 (2016).
Nortley, R. et al. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science 365, eaav9518 (2019).
Merlini, M., Wanner, D. & Nitsch, R. M. Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer’s disease-related microvascular cerebral amyloid angiopathy. Acta Neuropathol. 131, 737–752 (2016).
Bennett, R. E. et al. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 115, E1289–E1298 (2018).
Blair, L. J. et al. Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol. Commun. 3, 8 (2015).
Sagare, A. P. et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4, 2932 (2013).
Nation, D. A. et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25, 270–276 (2019).
Duan, L. et al. PDGFRβ cells rapidly relay inflammatory signal from the circulatory system to neurons via chemokine CCL2. Neuron 100, 183–200.e8 (2018).
Pluvinage, J. V. & Wyss-Coray, T. Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration. Nat. Rev. Neurosci. 21, 93–102 (2020).
Rabin, J. S. et al. Vascular risk and β-amyloid are synergistically associated with cortical tau. Ann. Neurol. 85, 272–279 (2019).
Mattson, M. P. & Arumugam, T. V. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 27, 1176–1199 (2018).
Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019).
Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004).
Suberbielle, E. et al. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat. Neurosci. 16, 613–621 (2013).
Sykora, P. et al. DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res. 43, 943–959 (2015).
Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).
Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018).
Bodea, L. G. et al. Accelerated aging exacerbates a pre-existing pathology in a tau transgenic mouse model. Aging Cell 16, 377–386 (2017).
Marschallinger, J. et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194–208 (2020).
Zullo, J. M. et al. Regulation of lifespan by neural excitation and REST. Nature 574, 359–364 (2019).
Brawek, B. et al. Impairment of in vivo calcium signaling in amyloid plaque-associated microglia. Acta Neuropathol. 127, 495–505 (2014).
We are grateful to S. S. Harris for his support preparing this manuscript, and we thank B. I. Lee for help with the figures. We acknowledge the donors of Alzheimer’s Disease Research (ADR), a program of BrightFocus Foundation, for the generous support of this research (grant number: A2019112S). M.A.B. is further supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd., funded by the Medical Research Council, Alzheimer’s Society and Alzheimer Research UK and by a UKRI Future Leaders Fellowship (grant number: MR/S017003/1). B.T.H. is supported by the Massachusetts Alzheimer’s Disease Research Center (P30AG062421), the JPB foundation, the National Institutes of Health (R01AG058674) and the Tau Consortium.
The authors declare no competing interests related to this project.
Peer review information Nature Neuroscience thanks Tong Li and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Busche, M.A., Hyman, B.T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci (2020). https://doi.org/10.1038/s41593-020-0687-6