BRAIN COMMUNICATIONS 2023: Page 1 of 4 | 1 BRAIN COMMUNICATIONS SCIENTIFIC COMMENTARY Is phosphorylated tau a good biomarker of synapse pathology in Alzheimer’s disease? Downloaded from https://academic.oup.com/braincomms/article/5/3/fcad142/7145699 by guest on 11 May 2023 This scientific commentary refers to a flourishing period of investigation symptomatic stages of the disease.4,6 ‘Distinct brain pathologies associated on novel brain imaging technologies However, despite the usefulness of with Alzheimer’s disease biomarker- and biomarkers for diagnosis and p-tau as potential biomarker of related phospho-tau 181 and phospho-tau prognosis of Alzheimer’s disease.1 A Alzheimer’s disease, their predictive 217 in App knock-in mouse models of reliable molecular biomarker that pre­ value for age-related cognitive decline amyloid-β amyloidosis’ by Hirota et al. dicts later cognitive decline during in the absence of dementia remains (https://doi.org/10.1093/braincomms/ physiological aging or preclinical de­ largely unclear. In this regard, the re­ fcac286) and ‘Predictive blood biomarkers mentia stages is undoubtedly critical cent article in Brain Communications and brain changes associated with for accurate disease detection and by Saunders et al.7 revealed a signifi­ age-related cognitive decline’ by Saunders timely diagnosis, which is necessary cant association of elevated baseline et al. (https://doi.org/10.1093/brain for widening the therapeutic window plasma p-tau181, NfL and GFAP, comms/fcad113). and improving the design of clinical but not Aβ42/40, with greater cogni­ Alzheimer’s disease is the most com­ trials. With this idea in mind, several tive decline ∼10 years later, whereas mon cause of dementia and disability in recent studies have pointed at plasma increase of p-tau 181 over time pre­ the elderly affecting currently 57 million levels of Aβ42/40, phosphorylated dicted cognitive decline even after cor­ people worldwide. The number of people tau (p-tau), neurodegeneration [neuro­ recting for APOE status and an suffering from the disease is expected to filament light (NfL)] and astrocyte re­ Alzheimer’s disease polygenic risk increase in the next decades if no effective activity [glial fibrillary acidic protein score. Considering the significant asso­ therapies based on pathological mechan­ (GFAP)] molecules as promising ciation of plasma p-tau 181 and 217 isms are developed. Classical therapeutic aging-dependent biomarkers that cor­ with cognitive decline in cognitively treatments (e.g. acetylcholinesterase inhi­ relate with cerebral Aβ and tau path­ unimpaired individuals and the conver­ bitors) only temporally alleviate some ologies and represent the core of the sion to pre-symptomatic Alzheimer’s cognitive and behavioural symptoms new recognized ATN (amyloid/tau/ disease,3,6–8 p-tau species may be con­ but without preventing disease progres­ neurodegeneration)-based diagnosis.2 sidered good predictors of memory sion, and new disease-modifying treat­ Accurate analysis of these biomarkers, loss at Alzheimer’s disease preclinical ments targeting amyloid-β (Aβ) (e.g. alone or in combination, in CSF or stages. Interestingly, pathological tau immunotherapy) show still limited thera­ plasma in parallel with brain positron oligomers and mature neurofibrillary peutic benefits in clinical studies even in emission tomography (PET) of amyl­ tangles is phosphorylated in multiple mild cognitive impairment (MCI) and oid and/or tau distinguishes people at Ser/Thr residues, so it is reasonable to moderate disease stages. Importantly, preclinical, MCI and/or dementia speculate that brain-derived plasma any new effective disease-modifying stages, and predicts, in some cases, fu­ tau proteins may contain several phos­ treatment should be administered as ture cognitive decline in cognitively phorylated sites. At present, however, early during disease progression as pos­ unimpaired elderly individuals.3 the specific plasma tau species contain­ sible, which requires development of ac­ Plasma p-tau at Thr 181 and 217 is ing unique or combination of phos­ curate and sensitive biomarkers. positively associated with cerebral phorylation sites (181, 217 or others An impressive research mainstream measurements of Aβ- and tau-PET pathological residues) that represent in the field has lately focused on the as­ imaging in Alzheimer’s disease the best predictors of cognitive decline sessment of changes of Alzheimer’s compared to cognitively unimpaired in aging and Alzheimer’s disease are disease-related pathological molecules controls or frontotemporal lobar de­ unknown. Phospho-proteomics ap­ in brain tissue and biofluids (e.g. CSF generation,4,5 and correlate with cog­ proaches may be useful to and blood/plasma), which has opened nitive deterioration in preclinical and identify specific p-tau protein species Received April 11, 2023. Revised April 11, 2023. Accepted April 25, 2023. Advance access publication April 27, 2023 © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2 | BRAIN COMMUNICATIONS 2023: Page 2 of 4 Scientific Commentary present in plasma during biological temporal cortex of Alzheimer’s disease and 3D reconstructions of brain cor­ and pathological aging. This could be patients compared to aged controls.7 tical sections of App knock-in mice. an important step for fine-tuning de­ We and others demonstrated that the According to their results, p-tau 181, velopment of tau biomarkers for ac­ presence of neuronal p-tau at synapses 217, 231, 202/205/208 species around curate diagnosis and prognosis in the and its accumulation in glial cells was as­ amyloid plaques do not accumulate in future. sociated with synapse dysfunction in dystrophic neurites or processes of glial Tau phosphorylation and aggrega­ memory neural circuits in Alzheimer’s cells (microglia, astrocytes and oligo­ tion are dynamic processes, and its re­ disease brain and mouse models.9 dendrocytes). On the contrary, p-tau lease into the CSF and blood are However, the contribution of synaptic 217 and 231 and 202/205/208, and to mediated, among others, by neuronal p-tau 181—alone or combined with a lesser extend p-tau 181, colocalized activity, exocytosis and secretory me­ other pathological-related phosphoryl­ with the postsynaptic glutamatergic chanisms, with glial cells playing an un­ ation sites (e.g. p-tau 217, 231, …)—to marker PSD95 but not with the cyto­ Downloaded from https://academic.oup.com/braincomms/article/5/3/fcad142/7145699 by guest on 11 May 2023 clear role. It is interesting that p-tau 181 synapse pathology and memory loss is matrix presynaptic protein Bassoon is accumulated in some neurofibrillary still unclear. To untangle this complex or other specific presynaptic neuro­ tangles, neuronal dystrophic neurites puzzle, Hirota et al.10 performed ex­ transmitter proteins of glutamatergic, around plaques and synapses in tensive immunofluorescence staining GABAergic, cholinergic or Figure 1 Cellular localization of phosphorylated and aggregated tau in the brain during aging and Alzheimer’s disease. The cellular distribution of aggregated and phosphorylated tau species (p-tau: Thr 181, 217 and 231) in the brain during aging and Alzheimer’s disease is shown. Synaptic and neuritic p-tau and Aβ released to the extracellular space are captured by glial cells (microglia and astrocytes) and they could be the source of tau and Aβ species found in cerebral and peripheral biofluids (CSF and blood). Scientific Commentary BRAIN COMMUNICATIONS 2023: Page 3 of 4 | 3 serotoninergic synapses.10 The authors astrocytes, as observed in mice.9 https://doi.org/10.1093/braincomms/fcad suggest that these pathological p-tau Although premature, it is tempting to 142 species accumulate abnormally at post­ speculate that enhanced release of tau synaptic sites in response to Aβ plaques (and Aβ) by dysfunctional synapses in App knock-in mice. In contrast, and/or deficient endocytosis and clear­ Funding Saunders et al.7 used high resolution ance of tau by astrocytes and microglia array tomography to detect increased could lead to extracellular tau accumu­ This work was supported by grant accumulation of p-tau 181 at lation and propagation resulting in its projects from Agencia Estatal de synaptophysin-labelled presynaptic release to central and peripheral fluids Investigación at Ministerio de Ciencia terminals in the human temporal cortex in Alzheimer’s disease. If this is the e Innovación of Spain (PID2019- from Alzheimer’s disease patients. case, synapses could be considered the 106615RB-I00 with FEDER funds Interestingly, they also identified p-tau source of p-tau and Aβ species used and PDC2021-121350-I00), Instituto de Salud Carlos III (CIBERNED Downloaded from https://academic.oup.com/braincomms/article/5/3/fcad142/7145699 by guest on 11 May 2023 181 in astrocytes and dystrophic neur­ currently as fluid biomarkers for ites around plaques in the temporal cor­ Alzheimer’s disease. This hypothetical CB06/05/0042), Generalitat de tex, detecting a significant increase of model of neuronal toxic tau and Aβ re­ Catalunya (2021 SGR00142) and plaques surrounded by astrocytes and lease to circulating biofluids is depicted BrightFocus Foundation (A202204 neurites containing p-tau 181 in in Fig. 1. Remarkably, if current tau im­ 7S). A.P.D is supported by the Juan Alzheimer’s disease cases compared munotherapies target synaptic tau, they de la Cierva-Incorporación program to healthy aging controls.7 Despite may be highly beneficial for lowering from Agencia Estatal de Investigación discrepancy about p-tau presynaptic lo­ trans-synaptic tau propagation and cir­ (IJC2019-042468-I). calization, both studies highlight the culating tau levels. In conclusion, these possibility of synaptic p-tau species as recent studies provide convincing evi­ potential biomarkers, adding import­ dence that p-tau biomarkers correlate Competing ant building blocks on our understand­ with synaptic tau accumulation and ing of the relationship between tau and cognitive decline in both Alzheimer’s interests synapse dysfunction. However, they disease and non-demented cohorts, The authors declare no financial inter­ have some limitations, including the ne­ further suggesting that targeting synap­ ests or potential conflicts of interest in cessity to validate these findings in hu­ tic tau pathology could be a relevant relation to the work presented in this man brain in early vulnerable regions therapeutic strategy for preventing cog­ study. (hippocampus, entorhinal cortex, …) nitive decline in Alzheimer’s disease at different disease stages. and aging. Intriguingly, the exact link between synaptic p-tau and tau in biofluids re­ Carlos A. Saura1,2,† and References 1. Leuzy A, Cullen NC, Mattsson-Carlgren mains unclear. Is synaptic p-tau the Arnaldo Parra-Damas1,2,† N, Hansson O. Current advances in plas­ source of tau in cerebral or peripheral 1 Departament de Bioquímica i Biologia ma and cerebrospinal fluid biomarkers in biofluids? What is the role of astrocytes Molecular, Institut de Neurociències, Alzheimer’s disease. Curr Opin Neurol. and microglia in synaptic tau release Facultat de Medicina, Universitat 2021;34(2):266-274. and accumulation in biofluids? Are Autònoma de Barcelona, Bellaterra 08193, 2. Jack CR J, Wiste HJ, Weigand SD, et al. Age-specific and sex-specific prevalence similar synaptic mechanisms involved Spain of cerebral β-amyloidosis, tauopathy, in extracellular Aβ42 release in brain 2 Centro de Investigación Biomédica en and neurodegeneration in cognitively un­ and biofluids? Neuronal and synaptic Red Enfermedades Neurodegenerativas impaired individuals aged 50–95 years: A activities increase tau release from (CIBERNED), Instituto de Salud Carlos cross-sectional study. Lancet Neurol. neurons, promoting tau propagation III, Madrid 28029, Spain 2017;16(6):435-444. 3. Janelidze S, Mattsson N, Palmqvist S, et al. across neural circuits, a result that Plasma P-tau181 in Alzheimer’s disease: strongly suggests that synapses can be Correspondence to: Carlos A. Saura, Relationship to other biomarkers, differ­ the source or responsible, at least in Institut de Neurociències, Facultat de ential diagnosis, neuropathology and lon­ part, of extracellular tau and p-tau. Medicina M2-113, Universitat Autònoma gitudinal progression to Alzheimer’s Extracellular tau could be captured by de Barcelona, Av Can Domenech s/n, dementia. Nat Med. 2020;26(3):379-386. 4. Ashton NJ, Janelidze S, Mattsson- glial cells, such as microglia and astro­ Barcelona, Spain 08193 Carlgren N, et al. Differential roles of cytes, that actively participate in tripar­ E-mail: carlos.saura@uab.cat Aβ42/40, p-tau231 and p-tau217 for tite or quadripartite synapses. Notably, Alzheimer’s trial selection and disease p-tau 181 is elevated in astrocytes of Correspondence may also be addressed to: monitoring. Nat Med. 2022;28(12): aged people with lifetime cognitive re­ Arnaldo Parra-Damas. 2555-2562. 5. Thijssen EH, La Joie R, Strom A, et al. silience compared with those with cog­ E-mail: arnaldo.parra@uab.cat Plasma phosphorylated tau 217 and nitive decline.7 The source of p-tau in phosphorylated tau 181 as biomarkers † astrocytes is unknown, but it is plausible These authors contributed equally to this in Alzheimer’s disease and frontotempor­ that secreted neuronal tau is captured by work. al lobar degeneration: A retrospective 4 | BRAIN COMMUNICATIONS 2023: Page 4 of 4 Scientific Commentary diagnostic performance study. Lancet brain changes associated with age-related aggregation in mice. Acta Neuropathol Neurol. 2021;20(9):739-752. cognitive decline. Brain Commun. 2023; Commun. 2021;9(1):162. 6. Karikari TK, Benedet AL, Ashton NJ, 5:fcad113. 10. Hirota Y, Sakakibara Y, Ibaraki K, Takei et al. Diagnostic performance and predic­ 8. Jonaitis EM, Janelidze S, Cody KA, K, Iijima K-M, Sekiya M. Distinct brain tion of clinical progression of plasma et al. Plasma phosphorylated tau 217 pathologies associated with Alzheimer’s phospho-tau181 in the Alzheimer’s dis­ in preclinical Alzheimer’s disease. Brain disease biomarker-related phospho-tau ease neuroimaging initiative. Mol Psych­ Commun. 2023;5:fcad057. 181 and phospho-tau 217 in App iatry. 2021;26(2):429-442. 9. Soto-Faguas CM, Sanchez-Molina P, knock-in mouse models of amyloid-β 7. Saunders TS, Pozzolo FE, Heslegrave A, Saura CA. Loss of presenilin function amyloidosis. Brain Commun. 2023;5: et al. Predictive blood biomarkers and enhances tau phosphorylation and fcac286. Downloaded from https://academic.oup.com/braincomms/article/5/3/fcad142/7145699 by guest on 11 May 2023