In situ cryoET of beta-amyloid and tau in post-mortem Alzheimer's disease brain
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ABSTRACT:
SUBMITTER: Rene Frank
PROVIDER: EMPIAR-12088 | biostudies-other |
REPOSITORIES: biostudies-other
Publications
CryoET of β-amyloid and tau within postmortem Alzheimer's disease brain.
Gilbert Madeleine A G MAG Fatima Nayab N Jenkins Joshua J O'Sullivan Thomas J TJ Schertel Andreas A Halfon Yehuda Y Wilkinson Martin M Morrema Tjado H J THJ Geibel Mirjam M Read Randy J RJ Ranson Neil A NA Radford Sheena E SE Hoozemans Jeroen J M JJM Frank René A W RAW
Nature 20240710 8022
A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures<sup>1</sup>. In Alzheimer's disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography ...[more]
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Project description:In-vivo labeling of retinal amyloid-beta(Aβ) and tau has potential as non-invasive biomarker for Alzheimer's disease (AD). However, literature on the presence of Aβ and phosphorylated tau (pTau) in AD retinas is inconclusive. We therefore assessed the presence of Aβ and pTau in post-mortem retinas in 6 AD and 6 control cases who donated brains and eyes to the Netherlands Brain Bank. Neuropathological diagnosis of AD was made according to NIA-AA criteria. Formalin fixed retinas were dissected in quadrants and cross-sections of medial and superior retinas were made. Immuno-histochemical stainings were performed for Aβ, amyloid precursor protein (APP) and pTau. To assess translation to an in-vivo set up using curcumin as labelling fluorophore, co-stainings with curcumin were performed. No typical Aβ-plaques and neurofibrillary tangles, like in the cerebral cortex, were observed in AD retinas. A diffuse immunoreactive signal for pTau was increased in the inner and outer plexiform layers of the retina in AD cases compared to control cases with absence of cerebral amyloid pathology. Immunostaining with anti-Aβ and anti-APP antibodies yielded signal in ganglion cells, amacrine cells, horizontal cells and Müller cells in both control and AD cases. We observed small extracellular deposits positive for anti-Aβ antibodies 12F4 and 6E10 and negative for 4G8 and curcumin. A subset of these deposits could be characterized as corpora amylacea. In conclusion we found that retinal manifestations of AD pathology appear to be different compared to cerebral AD pathology. Using a qualitative cross-sectional approach, we did not find Aβ/APP related differences in the retina between AD and control subjects. In contrast, tau related changes were found to be present in cases with cerebral AD pathology, suggesting retinal tau as a potential biomarker for AD.
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Project description:BackgroundAlzheimer's disease is a neurodegenerative condition associated with the accumulation of two misfolded proteins, amyloid-beta (A[Formula: see text]) and tau. We study their effect on neuronal activity, with the aim of assessing their individual and combined impact.MethodsWe use a whole-brain dynamic model to find the optimal parameters that best describe the effects of A[Formula: see text] and tau on the excitation-inhibition balance of the local nodes.ResultsWe found a clear dominance of A[Formula: see text] over tau in the early disease stages (MCI), while tau dominates over A[Formula: see text] in the latest stages (AD). We identify crucial roles for A[Formula: see text] and tau in complex neuronal dynamics and demonstrate the viability of using regional distributions to define models of large-scale brain function in AD.ConclusionsOur study provides further insight into the dynamics and complex interplay between these two proteins, opening the path for further investigations on biomarkers and candidate therapeutic targets in-silico.
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Project description:IntroductionWe aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers.MethodsCut points for Elecsys amyloid beta 42 (Aβ42), total tau (t-tau), hyperphosphorylated tau (p-tau), and t-tau/Aβ42 and p-tau/Aβ42 ratios were evaluated in Mayo Clinic Study of Aging (n = 804) and Mayo Clinic Alzheimer's Disease Research Center (n = 70) participants.ResultsThe t-tau/Aβ42 and p-tau/Aβ42 ratios had a higher percent agreement with normal/abnormal amyloid positron emission tomography (PET) than the individual CSF markers. Reciever Operating Characteristic (ROC)-based cut points were 0.26 (0.24-0.27) for t-tau/Aβ42 and 0.023 (0.020-0.025) for p-tau/Aβ42. Ratio cut points derived from other cohorts performed as well in our cohort as our own did. Individual biomarkers had worse diagnostic properties and more variable results in terms of positive and negative percent agreement (PPA and NPA).ConclusionCSF t-tau/Aβ42 and p-tau/Aβ42 ratios are very robust indicators of AD. For individual biomarkers, the intended use should determine which cut point is chosen.
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