. Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels. Acta Neuropathol Commun. 2022 Jan 6;10(1):3. PubMed.

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  1. Tau has a multitude of phosphorylation sites, many of which are increased in pathology, but the differential significance of specific p-tau variants in the AD pathogenic cascade is largely unknown. Recent reports indicate the potential of tau phosphorylated at threonine 217 as an early plasma biomarker that distinguishes AD from other tauopathies (Palmqvist et al., 2020). Increased p-tau217 is observed in the brain and CSF early during the progression of AD (Suárez-Calvet et al., 2020; Wesseling et al., 2020; Mattsson‐Carlgren et al., 2021) and has been suggested to connect amyloid and tau pathology. In this paper, Wennström et al. present an elegant first study that aims to link the pathological process in AD brain to p-tau217 plasma levels using two postmortem cohorts, an AD/control and an AD-/non-AD tauopathies cohort.

    Immunofluorescence analysis showed co-localization of p-tau217 with tau pathology in neurofibrillary tangles (NFTs) and neuropil threads (NTs), and it demonstrated increased intensity that was associated with the presence of amyloid plaques. Unexpectedly, unlike other p-tau epitopes, p-tau217 additionally accumulated in granulovacuolar degeneration bodies. GVBs are lysosomal structures that are induced in neurons upon the aggregation of tau (Wiersma et al., 2019). Their function is unknown. The abundance of p-tau217 in GVBs contrasts with the low abundance/absence of the other p-tau epitopes tested in this study (p-tau181, 202, 231, 202/205, and 369/404).

    Different p-tau epitopes have been reported previously in GVBs in postmortem tissue, albeit not consistently and often at low intensity (reviewed in Köhler, 2016). GVBs in our recently developed in vitro model (Wiersma et al., 2019) are negative for p-tau202/205 and 212/214. In addition, antibody-independent analysis does not show accumulation of overexpressed tau inside the experimental GVBs. It will be interesting to study whether the p-tau217 epitope is also selectively accumulating in the experimental GVBs, which would allow investigation of the earliest phase of GVB formation.

    Wennström et al. propose the attractive hypothesis that p-tau 217 in GVBs may be released from the neurons. GVBs in the human brain, as well as experimental GVBs, contain multivesicular body and exosome markers (Yamoah et al., 2020; Wiersma et al., 2020), which may suggest that GVB cargo can be actively secreted in response to neuronal tau pathology. This potentially provides an explanation for the presence of p-tau217 in CSF/plasma early in the pathogenic process and could be a potential source of seeds that may contribute to the spread of tau pathology.

    It was previously shown that tau phosphorylated at threonine 217 is not necessarily seed-competent (Wesseling et al., 2020). The seed-competence of p-tau217 in GVBs is currently unknown, but it may be relevant to note that the p-tau217-positive GVBs were not detected by the pFTAA probe, indicating that tau in GVBs has low β-sheet content. Experimental tau/GVB models will greatly facilitate functional investigation of the role of GVBs in generating the p-tau217 biomarker signal, including the opportunity to mechanistically address the observed association of P-tau217 with Aβ.

    References:

    . Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020 Aug 25;324(8):772-781. PubMed.

    . Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected. EMBO Mol Med. 2020 Dec 7;12(12):e12921. Epub 2020 Nov 10 PubMed.

    . Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease. Cell. 2020 Dec 10;183(6):1699-1713.e13. Epub 2020 Nov 13 PubMed.

    . Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau. EMBO Mol Med. 2021 Jun 7;13(6):e14022. Epub 2021 May 5 PubMed.

    . Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology. Acta Neuropathol. 2019 Dec;138(6):943-970. Epub 2019 Aug 27 PubMed.

    . Granulovacuolar degeneration: a neurodegenerative change that accompanies tau pathology. Acta Neuropathol. 2016 Sep;132(3):339-59. Epub 2016 Apr 9 PubMed.

    . Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer's Disease Brain. J Alzheimers Dis. 2020;75(1):139-156. PubMed.

    . Untangling the origin and function of granulovacuolar degeneration bodies in neurodegenerative proteinopathies. Acta Neuropathol Commun. 2020 Sep 3;8(1):153. PubMed.

  2. Neurons sickened by Alzheimer’s disease secrete telltale proteins, even at the earliest stages before the sickened neurons slowly die. Neurons in general, and sick neurons in particular, utilize an “unconventional” hatch to secrete proteins, specifically via the neuron’s endosomal system. It has long been known, for example, that AD neurons accelerate Aβ secretion via the multivesicular body—otherwise known as the “late endosome.” When late endosomes fuse with the neuron’s membrane, they secrete their contents.

    More recently, a growing body of evidence has established that tau, too, escapes neurons via endosomal secretion. In fact, accelerated tau secretion seems to be what distinguishes AD’s tauopathy from other tauopathies, such as FTD, which has even worse intraneuronal tangles.

    Previous elegant work by Ana Maria Cuervo and colleagues has solved the cellular topology problem about how tau, a cytosolic protein, can gain access to late endosomes. It does so via micro-autophagy. Previous work by Sabrina Simoes’ lab has shown that AD-associated defects in endosomal trafficking accelerate tau secretion, as detected in CSF.

    This work by Wennström et al. in many ways provides the missing part of the tau secretion puzzle: Among the many phosphorylated species of tau detected in biofluids, tau hyperphosphorylation at its 217 epitope appears to be most sensitive and specific to AD, even in its earliest stages. Why is p-tau217 in biofluids so diagnostic of AD?

    Wennström et al. answer this vexing question. Through a detailed and compelling series of investigations in AD tissue samples, they show that, compared to other p-tau species, p-tau217 is most reliably found in late endosomes. It makes sense that it is the one that is most likely to be secreted in the face of defects in endosomal trafficking; and it makes sense that p-tau217 is the most diagnostic since endosomal trafficking has emerged as a dominant biological pathway pathogenic in AD.

  3. Wennström et al. report the histopathological analysis of p-tau217 in AD, PART, and control brains and its correlation to plasma p-tau217. An interesting finding is that p-tau217 was not only observed in neurofibrillary tangles and neuropil threads but also in vesicles of granulovacuolar degeneration. Staining of granulovacuolar degeneration was not observed with other tau antibodies, although neurofibrillary tangles and neuropil threads were stained with the other phospho-tau antibodies as well. The relative levels of p-tau217 in six different cortical regions correlated with the respective Aβ plaque scores in the brain and the antemortem plasma p-tau 217 levels.

    1. This study validates the plasma biomarker p-tau217 as properly reflecting underlying brain tau pathology. Even though PART, intermediate-, and high-AD pathology cases are distinct, with these samples a correlation between tau and Aβ pathology was detected as previously reported by others using similar cohorts (e.g., Thal et al., 2019). The postmortem validation of plasma p-tau217 is an important step for the establishment of plasma tau measures as valid biomarkers in the clinical diagnostic procedures.

    2. From the view of a neuropathologist, another very interesting finding is that p-tau217 was seen in granulovacuolar degeneration lesions. Although tau was already reported to accumulate in these lesions (Dickson et al., 1987), the importance of this finding is that that plasma p-tau217 may not only reflect neurofibrillary tangles and neuropil threads, but also granulovacuolar degeneration.

    3. Moreover, Wennström et al. showed an increase of granulovacuolar degeneration with neurofibrillary tangle and neuropil thread pathology in moderate AD, whereas in severe AD granulovacuolar degeneration lessened with increasing neurofibrillary tangles and neuropil threads. Recently, we reported that granulovacuolar degeneration correlated with expression of the activated necrosome complex (pRIPK1, pRIPK3, pMLKL). This is the executor complex for necroptosis-driven programmed cell death, and its presence correlated with neuron loss in AD cases (Koper et al., 2020). The decrease of granulovacuolar degeneration with increasing neurofibrillary tangle pathology in severe AD may reflect the reduction of neuronal death at the moment when most neurons in the CA1 region, as assessed in this study, had already died, whereas ghost tangles and neurofibrillary tangles could still be detected in increasing amounts. Further research is required to better understand whether granulovacuolar degeneration and its associated necrosome accumulation reflect dying/agonal neurons in end-stage AD, when most neurons, for example in CA1, have already died.

    In summary, Wennström et al. validated p-tau217 in a postmortem cohort as a biomarker reflecting not only neurofibrillary tangle and neuropil thread pathology but also granulovacuolar degeneration. This supports the clinical validity of plasma p-tau217 measurements as an AD biomarker.

    References:

    . A monoclonal antibody that recognizes a phosphorylated epitope in Alzheimer neurofibrillary tangles, neurofilaments and tau proteins immunostains granulovacuolar degeneration. Acta Neuropathol. 1987;73(3):254-8. PubMed.

    . Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer's disease. Acta Neuropathol. 2020 Mar;139(3):463-484. Epub 2019 Dec 4 PubMed.

    . Different aspects of Alzheimer's disease-related amyloid β-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia. Acta Neuropathol Commun. 2019 Nov 14;7(1):178. PubMed.

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