Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life

Uhlmann, Ruth E.; Rother, Christian; Rasmussen, Jay; Schelle, Juliane; Bergmann, Carina; Gavilanes, Emily M. Ullrich; Fritschi, Sarah K.; Buehler, Anika; Baumann, Frank; Skodras, Angelos; Al-Shaana, Rawaa; Beschörner, Natalie; Ye, Lan; Kaeser, Stephan A.; Obermüller, Ulrike; Christensen, Søren; Kartberg, Fredrik; Stavenhagen, Jeffrey B.; Rahfeld, Jens‐Ulrich; Cynis, Holger; Qian, Fang; Weinreb, Paul H.; Bussière, Thierry; Walker, Lary C.; Staufenbiel, Matthias; Jucker, Mathias

doi:10.1038/s41593-020-00737-w

Cited by 67 publications

(68 citation statements)

References 57 publications

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“…The present study suggests that plasma p-tau231 may be superior at this task (AUC p-tau231 = 0.83 versus AUC = 0.77 p-tau181 in this study or AUC p-tau181 = 0.70 as reported by Karikari et al [ 27 ]). However, recent in vitro evidence demonstrates that pre-clinical AD may appear as a consequence of a much earlier pathogenic events, prior any in vivo detection of Aβ aggregation, and by reducing the concentration of Aβ during a “ pre-amyloid ” phase halts Aβ plaque formation and AD onset [ 63 ]. Therefore, the pre-clinical phase of AD maybe a too advanced state in the disease course for the therapeutic agent to optimally target the most pathogenic phase of the disease.…”

Section: Discussionmentioning

confidence: 99%

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

et al. 2021

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The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer’s disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92–0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-β negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β PET quartiles 2–4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3–4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I–II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-β deposition, prior to the threshold for amyloid-β PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-β positivity or apparent entorhinal tau deposition.

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Section: Discussionmentioning

confidence: 99%

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

et al. 2021

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“…This is more apparent for CSF p-tau231, which changes with Aβ deposition in the medial orbitofrontal, precuneus and posterior cingulate cortices before Aβ PET positivity is achieved. Thus, one could propose that increases in CSF p-tau231 are related to early Aβ seeds and could act as a key biomarker for the recently described "preamyloid phase" of AD, which occurs before Aβ deposition threshold 30 . CSF p-tau231 has been widely reported as a biomarker to detect AD at both the MCI and dementia stages of disease 11,[47][48][49][50][51] but often it has been concluded these changes are not different from CSF p-tau181 when directly compared 52 .…”

Section: Discussionmentioning

confidence: 99%

“…7). Speci cally, CSF p-tau231 becomes abnormal rst and seems the principal candidate to identify early Aβ seeds in the recently proposed "pre-amyloid phase" 30 , which is currently seen as the optimal period for therapeutic intervention. As Aβ accumulates toward Aβ positivity, other p-tau epitopes (p-tau217 and p-tau181) then become abnormal.…”

Section: Discussionmentioning

confidence: 99%

“…This is of fundamental importance for identifying individuals with subtle AD-related preclinical brain changes for therapeutic trials, as it anticipates which disease-modifying drug candidates have a better opportunity to show effectiveness if initiated before symptom onset or even before the threshold of Aβ positivity has been achieved. Indeed, a recent study in transgenic mice suggests that early removal of Aβ seeds, before Aβ deposition becomes detectable, led to a signi cant reduction of Aβ accumulation and downstream pathologies 30 . This emphasizes the need of a biomarker for detecting early Aβ seeds or the "pre-amyloid" phase.…”

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease

Ashton

Benedet

Pascoal

et al. 2021

Preprint

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Biomarkers for early phosphorylation of tau constitute an unmet need for disease modifying intervention in early stages of Alzheimer’s disease (AD). Recent advances in targeted mass spectrometry and immunoassays have revealed phosphorylation sites, in the cerebrospinal fluid (CSF), with potentially greater utility as preclinical and diagnostic biomarkers as compared to the well validated biomarker – phosphorylated tau at threonine 181 (p-tau181). Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are highly accurate biomarkers for Alzheimer’s disease (AD) neuropathology and are already increased before cognitive symptoms have manifested. However, it is unknown if these preclinical increases transpire earlier, prior to amyloid-beta (Aβ) positivity threshold, and if an ordinal sequence of p-tau epitopes occurs at this incipient phase. In this study, we measured cerebrospinal (CSF) p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum compared to AD neuropathology as indexed by Ab ([18F]AZD4694) and tau ([18F]MK6240) position emission tomography. CSF P-tau217 and p-tau231 predicted Aβ and tau at the preclinical and dementia stages to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was more sensitive to the earliest changes in Aβ in the medial orbitofrontal, precuneus and posterior cingulate cortices before global Aβ PET positivity had been achieved. Our findings demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application.

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“…Indeed, Aβ42 peptide immunization studies in AD patients have revealed that Aβ43-positive plaques can be cleared without a concomitant increase in vascular Aβ43 deposition [ 28 ], and the increased Aβ43 levels generated by mutant presenilin-1 alleles can be counteracted using small molecule γ-secretase modulators [ 89 ]. The therapeutic antibody aducanumab, which selectively recognizes Aβ aggregates including soluble oligomers and insoluble fibrils [ 81 ], is able to intercept early pre-amyloid Aβ seeds and reduce the development of cerebral Aβ pathology in mice [ 90 ], revealing that targeting Aβ seeds may have clinical benefit in AD patients.…”

Section: Discussionmentioning

confidence: 99%

Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice

Ruiz-Riquelme

Mao

Barghash

et al. 2021

acta neuropathol commun

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When injected into genetically modified mice, aggregates of the amyloid-β (Aβ) peptide from the brains of Alzheimer’s disease (AD) patients or transgenic AD mouse models seed cerebral Aβ deposition in a prion-like fashion. Within the brain, Aβ exists as a pool of distinct C-terminal variants with lengths ranging from 37 to 43 amino acids, yet the relative contribution of individual C-terminal Aβ variants to the seeding behavior of Aβ aggregates remains unknown. Here, we have investigated the relative seeding activities of Aβ aggregates composed exclusively of recombinant Aβ38, Aβ40, Aβ42, or Aβ43. Cerebral Aβ42 levels were not increased in AppNL−F knock-in mice injected with Aβ38 or Aβ40 aggregates and were only increased in a subset of mice injected with Aβ42 aggregates. In contrast, significant accumulation of Aβ42 was observed in the brains of all mice inoculated with Aβ43 aggregates, and the extent of Aβ42 induction was comparable to that in mice injected with brain-derived Aβ seeds. Mice inoculated with Aβ43 aggregates exhibited a distinct pattern of cerebral Aβ pathology compared to mice injected with brain-derived Aβ aggregates, suggesting that recombinant Aβ43 may polymerize into a unique strain. Our results indicate that aggregates containing longer Aβ C-terminal variants are more potent inducers of cerebral Aβ deposition and highlight the potential role of Aβ43 seeds as a crucial factor in the initial stages of Aβ pathology in AD.

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Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life

Cited by 67 publications

References 57 publications

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease

Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice

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