Age-dependent accumulation of tau aggregation in Caenorhabditis elegans

Abstract

Aging is the primary risk factor for Alzheimer’s disease (AD) and related disorders (ADRDs). Tau aggregation is a hallmark of AD and other tauopathies. Even in normal aging, tau aggregation is found in brains, but in disease states, significantly more aggregated tau is present in brain regions demonstrating synaptic degeneration and neuronal loss. It is unclear how tau aggregation and aging interact to give rise to the phenotypes observed in disease states. Most AD/ADRD animal models have focused on late stages, after significant tau aggregation has occurred. There are fewer where we can observe the early aggregation events and progression during aging. In an attempt to address this gap, we created C. elegans models expressing a GFP-tagged version of the human tau protein. Here we examined how tau-gfp behaved during aging, comparing wild-type tau (hTau40), a disease-associated mutation (P301S), and an aggregation-prone variant (3PO). We measured age-dependent changes in GFP intensity and correlated those changes to normal aging in the nematode. We found differences in tau stability and accumulation depending on the tau variant expressed. hTau40GFP and P301SGFP were localized to axons and cell bodies, while 3POGFP was more concentrated within cell bodies. Expression of 3POGFP resulted in decreased lifespan and variations in locomotor rate, consistent with a pathological effect. Finally, we found that the human tau interacted genetically with the C. elegans ortholog of human tau, ptl-1, where the loss of ptl-1 significantly accelerated the time to death in animals expressing 3PO.

Serum Oligomeric α-Synuclein and p-tau181 in Progressive Supranuclear Palsy and Parkinson’s Disease

“…PSP is also characterized by late-age onset, with pathological features including neuronal loss, gliosis, and accumulation of misfolded tau protein [55]. Similar to α-synuclein oligomers, tau aggregation and spreading also increase with aging [56,57], while the levels of soluble tau protein decrease [58]. Overall, our and previous findings support the associations between protein levels in body fluids and aging, highlighting the importance of considering age in biomarker studies.…”

Transgenic Dendra2::tau expression allows in vivo monitoring of tau proteostasis in Caenorhabditis elegans

“…C. elegans is an ideal organism for in vivo visualization of fluorescently tagged proteins owing to its optical transparency. Recently, Nunez et al (2022) presented a GFP-tagged tau C. elegans model that differs substantially from our Dendra2::tau model in that it (1) is expressed under the rgef-1 promoter, (2) fuses GFP to the C-terminus of tau, (3) lacks a disease phenotype without aging and (4) lacks visible tau aggregates. Since the initial description of Dendra2 as a photoconvertible protein in 2006 ( Gurskaya et al, 2006 ), Guha et al (2020) are the only other group to use Dendra2::tau as a probe for studying tau function and pathogenesis in C. elegans .…”

Aging, NRF2, and TAU: A Perfect Match for Neurodegeneration?

“…Through posttranslational modifications (PTMs), mainly phosphorylation, the TAU protein can have its functionality altered and become prone to aggregate. It has been described that TAU aggregation accumulated in an age-dependent manner in a Caenorhabditis elegans ( C. elegans ) model [ 96 ]. In contrast, in human brain samples, it has been described that total soluble TAU levels declined with age [ 97 ].…”