Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model

In AD models, absence of tau rescues behavioral impairments and reduces neurotoxicity despite no significant changes in Aβ levels.

“For example, in AD models, the absence of tau has been shown to rescue behavioral impairments and reduce neurotoxicity, despite no significant changes in Aβ levels [75–79].”

In multiple mouse disease models, tau ablation is associated with protective effects.

“Interestingly, in multiple mouse disease models, tau ablation has been associated with protective effects.”

Tau ablation confers neuronal protection resulting in the recovery of behavioral deficits in neurodegenerative and neurodevelopmental models.

“Numerous studies across neurodegenerative and neurodevelopmental models have shown that tau ablation confers neuronal protection resulting in the recovery of behavioral deficits [56, 75, 76, 121–123].”

Across various animal models that exhibit epilepsy, reducing tau levels reduces network hyperexcitability, seizure severity, and latency to seizure stages.

“Across various animal models that exhibit epilepsy, reducing tau levels reduces network hyperexcitability, seizure severity, and latency to seizure stages (Roberson et al., 2007; Ittner et al., 2010; DeVos et al., 2013; Holth et al., 2013; Wang and Mandelkow, 2016; Ali et al., 2019).”

Tau-Fyn interaction in synapses is required to induce pathology in mice over-expressing APP, where reduced Tau levels decrease excitotoxicity and reduced Fyn levels prevent Aβ toxicity.

“Moreover, Tau–Fyn interaction in synapses has been shown to be required to induce pathology in mice over-expressing APP, where reduced Tau levels decrease excitotoxicity and reduced Fyn levels prevent Aβ toxicity [104].”

Reducing tau levels prevents Aβ-induced cognitive deficits and premature mortality, reduces spontaneous and induced seizure activity, and prevents synaptic impairment in mutant APP-expressing mouse models.

“Reducing tau levels prevents Aβ-induced cognitive deficits and premature mortality, reduces spontaneous and induced seizure activity, and prevents synaptic impairment in mutant APP-expressing mouse models (Roberson et al., 2007, 2011).”

Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis that lies upstream of tau-induced neurodegeneration.

“Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis [2–8] that lies upstream of tau-induced neurodegeneration [3, 5, 9, 10].”

APP transgenic mice lacking tau develop Aβ pathology but remain cognitively normal.

“Neurons without tau are resistant to Aβ toxicity, and APP transgenic mice lacking tau develop Aβ pathology but remain cognitively normal (Rapoport et al., 2002; Roberson et al., 2007).”

Neurons without tau are resistant to Aβ toxicity.

“Neurons without tau are resistant to Aβ toxicity, and APP transgenic mice lacking tau develop Aβ pathology but remain cognitively normal (Rapoport et al., 2002; Roberson et al., 2007).”

Data from cell and animal models show that tau is a mediator of Aβ-induced toxicity.

“Data from cell and animal models show that tau is also a mediator of Aβ-induced toxicity46–48.”

Some data suggest that Aβ toxicity is partially mediated through tau, as tau knockout mice are protected against Aβ-induced insults including cognitive effects, seizures, survival, axonal transport, and DNA double-stranded breaks.

“Some data suggest that Aβ toxicity is partially mediated through tau (50–52) as the tau knockout mouse has proven to be protected against a growing number of Aβ-induced insults, including those affecting cognition (50, 53), seizures (14, 50, 51, 54, 55), survival (50, 51, 54), axonal transport (52), and double-stranded breaks in DNA (55).”

Mice that completely lack tau have proven to be phenotypically normal in learning/memory and general cognition, with a minor motor phenotype developing later in life.

“Surprisingly, mice that completely lack tau have proven to be phenotypically normal in terms of learning/memory and general cognition (13, 14, 50) with a minor motor phenotype developing later in life, the severity of which varies (12–14, 56).”