Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss

Abstract

Neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau, are hallmarks of neurodegenerative diseases including Alzheimer disease (AD). In neurodegenerative diseases, neuronal dysfunction due to neuronal loss and synaptic loss accompanies NFT formation, suggesting that a process associated with NFT formation may be involved in neuronal dysfunction. To clarify the relationship between the tau aggregation process and synapse and neuronal loss, we compared two lines of mice expressing human tau with or without an aggregation-prone P301L mutation. P301L tau transgenic (Tg) mice exhibited neuronal loss and produced sarcosyl-insoluble tau in old age but did not exhibit synaptic loss and memory impairment. By contrast, wild-type tau Tg mice neither exhibited neuronal loss nor produced sarcosyl-insoluble tau but did exhibit synaptic loss and memory impairment. Moreover, P301L tau was less phosphorylated than wild-type tau, suggesting that the tau phosphorylation state is involved in synaptic loss, whereas the tau aggregation state is involved in neuronal loss. Finally, increasing concentrations of insoluble tau aggregates leads to the formation of fibrillar tau, which causes NFTs to form. NFTs2 are commonly observed in neurodegenerative disorders. Brain regions containing NFTs also exhibit neuronal loss. The rate of neuron loss is much greater than the rate of NFT formation, suggesting that NFT formation and neuronal death share a common mechanism (1, 2). This hypothesis is strongly supported by the discovery of tau gene mutations in individuals with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (3, 4). A single tau gene mutation induces NFT formation and neuronal loss with 100% penetration. Moreover, overexpression of human FTDP-17 tau induces NFT formation, neuronal loss, and behavioral deficits in mice (5-12).Mice that overexpress P301L mutant tau under the regulation of a tetracycline-inducible promoter display age-related NFTs, neuronal death, and behavioral deficits (13,14). Although inhibiting mutant tau overexpression in these mice blocks neuronal death and improves memory, NFTs continue to form (13,15). This suggests that NFTs are not themselves toxic but, instead, that NFT formation and neuronal death and neuronal dysfunction share a common underlying mechanism.The P301L tau mutation is known as an "aggregation-prone mutation" in that individuals harboring this mutation produce mutant tau that readily aggregates (16 -18). The NFTs of one patient with an aggressive FTDP-17 phenotype consisted of only P301L mutant tau (19), indicating that P301L mutant tau itself may possess a toxic function by forming aggregated tau.The formation of tau fibrils is believed to involve three sequential steps (20,21). First, monomeric tau binds together to form oligomers that are soluble in sarcosyl solution. The structure of these oligomers, however, is not discernible under atomic force microscopy. Second, as soluble tau oligomers take on a ␤-sheet structure, they form tau aggregat...

Stress Acts Cumulatively To Precipitate Alzheimer's Disease-Like Tau Pathology and Cognitive Deficits

“…Sarkosylinsoluble fractions from tissue protein extracts were prepared as previously described (Kimura et al, 2010). Briefly, frozen hippocampi of P301L tau mice were homogenized in Tris-buffered saline (10 mM Tris, 150 mM NaCl, pH 7.4) containing protease inhibitors (1 mg/ml antipain, 5 mg/ml pepstatin, 5 mg/ml leupeptin, 2 mg/ml aprotinin, and 0.5 mM 4-[2-aminoethyl]benzenesulfonyl fluoride hydrochloride) and phosphatase inhibitors (1 mM NaF, 0.4 mM Na 3 VO 4 , and 0.5 mM okadaic acid).…”

Adaptive responses to alloxan‐induced mild oxidative stress ameliorate certain tauopathy phenotypes

“…Considering the toxic nature of ROS, we would expect that some neurons were also damaged in the brain as a result of the alloxan injection. Meanwhile, our previous report suggested that the substantial neuronal losses observed in P301L TG mice are the consequence of insoluble tau accumulation (Kimura et al, 2010). Therefore, it is difficult to extrapolate how the alloxan-induced decrease in insoluble tau levels might influence neuronal numbers.…”

“…To test the impact of oxidative stress on the phenotypes associated with tau misfolding and dysfunction in vivo, we injected alloxan into TG mice that express human mutant (P301L) tau (Kimura et al, 2010). A single intraperitoneal injection of alloxan at 100 mg kg )1 of body weight, on average, failed to significantly change either blood glucose concentration or body weight ( Fig.…”

“…This is a reasonable premise because tau phosphorylation is thought to cause tau to detach from microtubules, which then become destabilized (Mi & Johnson, 2006;Ballatore et al, 2007). In turn, hyperphosphorylated tau eventually forms insoluble tau aggregates, which, perhaps in a prefibrillar state, induce synapse loss and memory deficits (Kimura et al, 2007(Kimura et al, , 2010. Therefore, anti-tauopathic properties of low-dose alloxan found in mouse models can be considered as an in vivo proof of concept that might be assumed from in vitro data, such as the dephosphorylation of tau as a result of acute oxidative stress (Davis et al, 1997;LoPresti & Konat, 2001;Zambrano et al, 2004).…”

“…The mice were derived from two lines that express human tau containing a mutation (P301L or R406W) associated with frontotemporal dementia with parkinsonism linked with chromosome 17 (FTDP-17) (Tatebayashi et al, 2002;Kimura et al, 2010). Expression of mutant human tau was driven by CaM kinase II promoter, as described previously (Tatebayashi et al, 2002;Kimura et al, 2010). The P301L cohort (P301L TG and NTG controls) consisted of only males, while the R406W cohort (R406W TG and NTG controls) consisted of both males and females at approximately a 1:1 ratio.…”