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Severe oligomeric tau toxicity can be reversed without long-term sequelae.

ABSTRACT: Tau is a microtubule stabilizing protein that forms abnormal aggregates in many neurodegenerative disorders, including Alzheimer's disease. We have previously shown that co-expression of fragmented and full-length tau in P301SxTAU62on tau transgenic mice results in the formation of oligomeric tau species and causes severe paralysis. This paralysis is fully reversible once expression of the tau fragment is halted, even though P301S tau expression is maintained. Whereas various strategies to target tau aggregation have been developed, little is known about the long-term consequences of reverted tau toxicity. Therefore, we studied the long-term motor fitness of recovered, formerly paralysed P301SxTAU62on-off mice. To assess the seeding competence of oligomeric toxic tau species, we also inoculated ALZ17 mice with brainstem homogenates from paralysed P301SxTAU62on mice. Counter-intuitively, after recovery from paralysis due to oligomeric tau species expression, ageing P301SxTAU62on-off mice did not develop more motor impairment or tau pathology when compared to heterozygous P301S tau transgenic littermates. Thus, toxic tau species causing extensive neuronal dysfunction can be cleared without inducing seeding effects. Moreover, these toxic tau species also lack long-term tau seeding effects upon intrahippocampal inoculation into ALZ17 mice. In conclusion, tau species can be neurotoxic in the absence of seeding-competent tau aggregates, and mice can clear these tau forms permanently without tau seeding or spreading effects. These observations suggest that early targeting of non-fibrillar tau species may represent a therapeutically effective intervention in tauopathies. On the other hand, the absent seeding competence of early toxic tau species also warrants caution when using seeding-based tests for preclinical tauopathy diagnostics.

SUBMITTER: Martinisi A

PROVIDER: S-EPMC8041046 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Critical neurologic disease and injury affect thousands of children annually with survivors suffering high rates of chronic morbidities related directly to the illness and to critical care hospitalization. Postintensive care syndrome (PICS) in patients and families encompasses a variety of morbidities including physical, cognitive, emotional, and psychological impairments following critical care. We conducted a focus group study with parents of children surviving pediatric neurocritical care (PNCC) for traumatic brain injury, stroke, meningitis, or encephalitis to determine outcomes important to patients and families, identify barriers to care, and identify potential interventions to improve outcomes. Sixteen parents participated in four groups across Oregon. Three global themes were identified: (1) PNCC is an intense emotional experience for the whole family; (2) PNCC survivorship is a chronic illness; and (3) PNCC has a significant psychological and social impact. Survivors and their families suffer physical, emotional, psychological, cognitive, and social impairments for many years after discharge. Parents in this study highlighted the emotional and psychological distress in survivors and families after PNCC, in contrast to most PNCC research focusing on physical outcomes. Several barriers to care were identified with potential implications on survivor outcomes, including limited pediatric resources in rural settings, perceived lack of awareness of PICS among medical providers, and the substantial financial burden on families. Parents desire improved education surrounding PICS morbidities for families and medical providers, improved communication with primary care providers after discharge, access to educational materials for patients and families, direction to mental health providers, and family support groups to assist them in dealing with morbidities and accessing appropriate resources. Clinicians and researchers should consider the parent perspectives reported here when caring for and evaluating outcomes for children requiring PNCC.

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Severe oligomeric tau toxicity can be reversed without long-term sequelae.

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