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New Biomarkers Catch Tau Before It Tangles | ALZFORUM Tau pathology in humans or animals, without fail, is made up of the hyperphosphorylated protein In AD tau is hyperphosphorylated sub-stoichiometrically at multiple sites by several combinations of protein kinases Six isoforms of tau in the human brain and hyperphosphorylation at multiple sites in AD generate numerous protein species
Cell-Based Assay Matches Tau Strains to Neuropathological Diagnosis Tau, Incorporated A library of tau mutants generated by alanine substitution (red residues, left), was transduced into biosensor cell lines containing pre-existing tau fibril strains The degree of incorporation of each mutant into the growing fibrils (middle) is measured via FRET (right) [Courtesy of Vaquer-Alicea et al , Science Advances
ApoE3 Christchurch Clings Tightly to Tau, Averting Tangles The authors argue that tight binding between ApoE3Ch and tau that prevents fragmentation, plus weak binding between ApoE3Ch and lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans, as reported previously, together prevent ApoE3Ch-bound tau from getting into neurons or microglia, stopping the spread of tau toxicity
Tau (AT8); Phospho Tau (Ser 202, Thr 205) | ALZFORUM Hyperphosphorylated tau polymerizes into paired helical filaments, which aggregate to form neurofibrillary tangles, one of the defining lesions of Alzheimer’s disease Recognizes paired helical filament (PHF) tau Phosphorylation at serine 202 and threonine 205 is required for recognition by AT8
Night-Night, Neurodegeneration: Sleep Aid Lulls Tau Pathology A different sleep drug, the GABA A modulator zolpidem, had no such effect, with mice bearing the full brunt of tau pathology (image below) Females, whose atrophy was milder, reaped little benefit from either therapy Goodnight, Degeneration: Vehicle-treated P301S E4 mouse show tau’s toll: swollen ventricles and a thinned hippocampus (left
Organization of Aβ Plaques and Tau Tangles Illuminated in AD Brain By contrast, tau aggregates were neatly ordered, with uniform, evenly spaced fibrils arranged into bundles Many of these tau filaments resembled the paired helical filaments characteristic of AD But surprisingly, others looked more like fibrils found in people with chronic traumatic encephalopathy (CTE)
Heavy Tau Snuffs Out Hippocampal Bursts | ALZFORUM Shushed by Tau Left: In patch-clamp setup, tau from AD brain is loaded into the recording pipette and diffuses into the CA1 neuron with which the pipette has made its seal Middle: Immunofluorescence image showing successful delivery of tau, with biocytin (green) marking the neuron, Tau-13 antibody staining infused tau (red)
MTBR-243 Tau: A Fluid Biomarker for Tangles Themselves? However, past tau biomarker studies didn’t find MTBR-tau in CSF, in part because the antibodies available at the time were insufficiently specific or sensitive They instead focused on the parts of tau they could detect, that is, the N-terminal and mid-domain, aka proline-rich region, which are actively secreted from neurons after truncation
Tau (CP-13) - ALZFORUM CP-13 immunotherapy has been tested in disease models, with limited success Passive immunization of JNPL3 mice, which express human tau with the P301L mutation, prevented the appearance of pathological forms of tau, although this effect depended upon the brain region and tau fraction examined (d’Abramo et al , 2015)
MAPT P301S - ALZFORUM Tau aggregates and oligomers may be the underlying cause of some of the disruptions For example, one study found that P301S tau aggregates interact with and mislocalize nuclear speckle components, disrupting mRNA splicing in mouse and cell models (Apr 2021 news; Lester et al , 2021)