Early Detection of Tau Pathology

While a definitive Alzheimer's disease (AD) diagnosis remains a post-mortem exercise, the ATN Research Framework proposed by the National Institute on Aging and the Alzheimer's Association utilizes a score representing the presence of amyloid deposits (A), tau deposits (T) and neuronal degeneration markers (N), with A+T+ necessary for a positive diagnosis. Current detection of tau pathology lags amyloid detection by years and by the time both markers are detected the disease is fairly advanced. We describe the development of a new generation of molecular imaging probes for in vivo detection of cells undergoing abnormal phosphorylation representing the initial stages of pTau pathology, potentially enabling a very early stage diagnosis of AD. We describe a novel nanoparticle formulation that binds such abnormally phosphorylating cells in a mouse model of tau pathology, enabling in vivo visualization of the hyperphosphorylative state by magnetic resonance imaging. Our results demonstrate the potential of this novel platform to identify a correlative marker signifying the development of future tau pathology, and has implications for early-stage diagnosis of Alzheimer's disease.

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Transcranial in vivo detection of amyloid-beta at single plaque resolution with large-field multifocal illumination fluorescence microscopy

10.1101/2020.02.01.929844 ◽

2020 ◽

Cited By ~ 2

Author(s):

Ruiqing Ni ◽

Zhenyue Chen ◽

Gloria Shi ◽

Alessia Villois ◽

Quanyu Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fluorescence Microscopy ◽

Amyloid Beta ◽

Large Field ◽

Microscopy Technique ◽

In Vivo Detection ◽

Amyloid Deposits ◽

Microscopy Techniques

AbstractThe abnormal deposition of beta-amyloid proteins in the brain is one of the major histopathological hallmarks of Alzheimer’s disease. Currently available intravital microscopy techniques for high-resolution plaque visualization commonly involve highly invasive procedures and are limited to a small field-of-view within the rodent brain. Here, we report the transcranial detection of amyloid-beta deposits at the whole brain scale with 20 μm resolution in APP/PS1 and arcAβ mouse models of Alzheimer’s disease amyloidosis using a large-field multifocal (LMI) fluorescence microscopy technique. Highly sensitive and specific detection of amyloid-beta deposits at a single plaque level in APP/PS1 and arcAβ mice was facilitated using luminescent conjugated oligothiophene HS-169. Immunohistochemical staining with HS-169, anti-Aβ antibody 6E10, and conformation antibodies OC (fibrillar) of brain tissue sections further showed that HS-169 resolved compact parenchymal and vessel-associated amyloid deposits. The novel imaging platform offers new prospects for in vivo studies into Alzheimer’s disease mechanisms in animal models as well as longitudinal monitoring of therapeutic responses at a single plaque level.

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P2-237: Novel 18F-labeled quinoline derivatives for in vivo detection of tau pathology in Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2012.05.944 ◽

2012 ◽

Vol 8 (4S_Part_9) ◽

pp. P343-P343

Author(s):

Nobuyuki Okamura ◽

Shozo Furumoto ◽

Ryuichi Harada ◽

Michelle Fodero-Tavoletti ◽

Victor Villemagne ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Quinoline Derivatives ◽

Tau Pathology ◽

In Vivo Detection

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Significant effects of cholinesterase inhibitors on tau pathology in the Alzheimer's disease continuum: An in vivo positron emission tomography study

International Journal of Geriatric Psychiatry ◽

10.1002/gps.5522 ◽

2021 ◽

Author(s):

Fumihiko Yasuno ◽

Hiroyuki Minami

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Positron Emission Tomography ◽

Cholinesterase Inhibitors ◽

Emission Tomography ◽

Positron Emission Tomography Study ◽

Tau Pathology ◽

Positron Emission

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P2-385: Binding and pharmacokinetic properties of novel 18 F-labeled agents for in vivo imaging of tau pathology in Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2010.05.1437 ◽

2010 ◽

Vol 6 ◽

pp. S429-S430

Author(s):

Nobuyuki Okamura ◽

Shozo Furumoto ◽

Katsutoshi Furukawa ◽

Hiroyuki Arai ◽

Kazuhiko Yanai ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

In Vivo Imaging ◽

Tau Pathology ◽

Pharmacokinetic Properties

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Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer’s disease trigger BACE1 accumulation in axonal swellings

Science Translational Medicine ◽

10.1126/scitranslmed.aba1871 ◽

2020 ◽

Vol 12 (570) ◽

pp. eaba1871

Author(s):

Selene Lomoio ◽

Rachel Willen ◽

WonHee Kim ◽

Kevin Z. Ho ◽

Edward K. Robinson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variant ◽

Late Onset ◽

Early Stage ◽

Loss Of Function ◽

Axonal Trafficking ◽

Axonal Swellings

Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer’s disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the β-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo. We show that BACE pharmacological inhibition ameliorates BACE1 axonal trafficking and diminishes axonal dystrophies in Gga3 null neurons in vitro and in vivo. These data indicate that axonal accumulation of BACE1 engendered by GGA3 loss of function results in local toxicity leading to axonopathy. Gga3 deletion exacerbates axonal dystrophies in a mouse model of AD before β-amyloid (Aβ) deposition. Our study strongly supports a role for GGA3 in AD pathogenesis, where GGA3 loss of function triggers BACE1 axonal accumulation independently of extracellular Aβ, and initiates a cascade of events leading to the axonal damage distinctive of the early stage of AD.

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Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-020-00404-5 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Garrett S. Gibbons ◽

Soo-Jung Kim ◽

Qihui Wu ◽

Dawn M. Riddle ◽

Susan N. Leight ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Monoclonal Antibodies ◽

Statistical Significance ◽

Neuritic Plaque ◽

Plaque Burden ◽

Primary Neurons ◽

Tau Pathology ◽

Model Of Alzheimer’S Disease

Abstract Background The spread of tau pathology in Alzheimer’s disease (AD) is mediated by cell-to-cell transmission of pathological tau seeds released from neurons that, upon internalization by recipient neurons, template the misfolding of naïve cellular tau, thereby propagating fibrillization. We hypothesize that anti-tau monoclonal antibodies (mAbs) that selectively bind to pathological tau seeds will inhibit propagation of tau aggregates and reduce the spread of tau pathology in vivo. Methods We inoculated mice with human AD brain-derived extracts containing tau paired helical filaments (AD-tau) and identified two novel mAbs, DMR7 and SKT82, that selectively bind to a misfolded pathological conformation of tau relative to recombinant tau monomer. To evaluate the effects of these mAbs on the spread of pathological tau in vivo, 5xFAD mice harboring significant brain Aβ plaque burden were unilaterally injected with AD-tau in the hippocampus, to initiate the formation of neuritic plaque (NP) tau pathology, and were treated weekly with intraperitoneal (i.p.) injections of DMR7, SKT82, or IgG isotype control mAbs. Results DMR7 and SKT82 bind epitopes comprised of the proline-rich domain and c-terminal region of tau and binding is reduced upon disruption of the pathological conformation of AD-tau by chemical and thermal denaturation. We found that both DMR7 and SKT82 immunoprecipitate pathological tau and significantly reduce the seeding of cellular tau aggregates induced by AD-tau in primary neurons by 60.5 + 13.8% and 82.2 + 8.3%, respectively, compared to IgG control. To investigate the mechanism of mAb inhibition, we generated pH-sensitive fluorophore-labeled recombinant tau fibrils seeded by AD-tau to track internalization of tau seeds and demonstrate that the conformation-selective tau mAbs inhibit the internalization of tau seeds. DMR7 and SKT82 treatment reduced hyperphosphorylated NP tau as measured with AT8 immunohistochemistry (IHC) staining, but did not achieve statistical significance in the contralateral cortex and SKT82 significantly reduced tau pathology in the ipsilateral hippocampus by 24.2%; p = 0.044. Conclusions These findings demonstrate that conformation-selective tau mAbs, DMR7 and SKT82, inhibit tau pathology in primary neurons by preventing the uptake of tau seeds and reduce tau pathology in vivo, providing potential novel therapeutic candidates for the treatment of AD.

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