Table 1.

Summary and key results of studies using tau knockout animals.

Tau KO animal	Experimental approach	Change in Tau KO animals	References
Scn1aRX/+ and Cntnap2−/− mice × Tau KO mice (Dawson)		Diminished epilepsy, abnormally enlarged brains, and $\text{overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B).}$	(17)
Tau KO mouse		Impaired contextual and cued fear memory.	(80)
Tau KO mouse	Fluid percussion injury	Lower anxiety and improved motor function after recovery.	(81)
Tau KO mouse		Decrease in functional extrasynaptic NMDA receptors in the hippocampus.	(82)
Transgenic mouse model of α-synucleinopathy (TgA53T) × Tau KO		Ameliorates cognitive dysfunction and concurrent $\text{synaptic deficits}$ of TgA53T mice.	(83)
Tau KO mice		Increased ATP production and improved recognition memory and attentive capacity of juvenile mice.	(84)
Tau KO mice		Olfactory deficit correlated with accumulation of α-synuclein and autophagic impairment.	(85)
Acute Tau KO		Impaired motor coordination and spatial memory.	(86)
Tau KO (tauΔex1)		Reduced susceptibility to excitotoxic seizures.	(87)
Tau KO on B6129PF3/J genetic background		Age-dependent short-term memory deficits, hyperactivity and synaptic plasticity defects.	(88)
Tau KO		Hyperglycemic and glucose intolerance; reduced islet insulin content and elevated proinsulin levels; increased epididymal fat mass and leptin levels; reduced glucose production, and insulin resistance at later ages, leading to complete onset of diabetes.	(89)
Transgenic (J20) mice express human amyloid precursor protein (hAPP) with the Swedish (K670N, M671L) and Indiana (V717F) mutations under the control of the PDGF β-chain promoter × Tau KO mice (Dawson)		$\text{Hippocampal hyperactivity,}$ but not mPFC hypoactivity, is attenuated by deletion of tau; tau depletion failed to reverse the memory impairment induced by over-production of APP in MWM; deletion of tau alleviated the hyperlocomotion displayed by APP transgenics.	(90)
Tau KO	Experimental stroke, using a middle cerebral artery occlusion with reperfusion model	$\text{Protection from excitotoxic brain damage}$ and neurological deficits.	(16)
Tau KO	Stress-driven suppression of neurogenesis	After exposure to chronic stress no reduction in DG proliferating cells, neuroblasts and newborn neurons.	(91)
Tau KO (Dawson)	Cortical cultures Treatment with extracellular tau	Much less affected $\text{transport of BDNF, BACE1 or NPY.}$	(92)
Tau KO (Dawson)		Heterozygous tau knockout, but not homozygous knockout, induced a $\text{selective loss of VTA DA neurons}$ at the early post-natal stage P0, which correlated with a similar reduction in Otx2 expression and $\text{increases in prenatal cell death}$ and the unactivated compensation effect of MAP1A in Mapt+/− mice.	(93)
Tau KO (Dawson)	Unilateral, transient middle cerebral artery occlusion (MCAO)	Mice were protected against hemispheric reperfusion injury following MCAO at 3-months of age but not at 12-months.	(94)
Tau KO (Tucker)		Impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations.	(95)
Tau KO mice (Dawson)		Increased locomotor activity in 5-months-old animals compared to human wild-type expressing animals.	(96)
Tau KO mice		Tau ablation blocks stress-driven anxious, anhedonic, and passive coping behaviors as well as cognitive impairments; chronic unpredictable stress decreased NA and 5HT levels in WT, but not Tau-KO, animals; stress-driven structural remodeling of hippocampal neurons depends on tau protein.	(15)
Tau KO mice (Dawson)	Primary cultures of hippocampal neurons	Tau is required for normal interactions of RNA binding proteins in brain tissue and tau promotes stress granules, while TIA1 promotes tau misfolding and insolubility.	(97)
Tau KO mice (Dawson)		$\text{Tau facilitates kainic acid (KA)-induced seizures }\mathrm{in vivo;}\text{tau facilitates ROS production in response to excitotoxic insult }\mathrm{in vivo}.$	(98)
Tau KO mice	Stereotactic injection of Aβ42 oligomers into the hippocampal dorsal CA1 area bilaterally	Protection against Aβ-induced cognitive impairment, $\text{hippocampal neuron loss,}$ and iron accumulation.	(99)
Tau KO mice	Primary cultures of cortical neurons	Protection of mouse primary cortical neurons from loss of mitochondrial membrane potential (ΔΨm) caused by low concentrations of Aβ42; absence of tau resulted in significantly greater $\text{increases in Ca}{}_{\text{cyt}}^{2+}$ in response to Aβ treatment.	(100)
Tau KO mice		$\text{Basal synaptic transmission of mossy fibers measured by input output curves is decreased;}$ $\text{bouton diameter increase of ~45\%.}$	(101)
Tau KO mice on Bl6/129sv and Bl6 backgrounds		Complete tau reduction impairs the performance of mice in accelerated Rotarod test, impairs the performance of mice in Pole test, impairs the performance of mice in Openfield test, alters hindlimb clasping behavior at 12 months of age; motor deficits are related to $\text{nigral degeneration.}$	(102)
Tau KO mice		Treatment with streptozotocin did not lead to impaired hippocampal cognitive behavior in Tau KO mice nor in reduction of PDS-95, synaptophysin and p-CREB.	(103)
Tau KO mice		$\text{Impaired LTD}$ but not LTP in Tau KO mice at 7–11 months of age.	(104)
Tau KO mice	Primary neurons	Tau deficiency prevents AβO-induced polyglutamylation, $\text{spastin recruitment,}$ and $\text{TTLL6 transport}$ into dendrites; tau deficiency does not protect against Aβ association to dendrites and transient spine loss, but $\text{protects against loss of MTs,}$ neurofilament invasion, and loss of mitochondria.	(105)
Tau KO mice (Dawson)	Primary cell culture	Tau is required in cultured neurons for ectopic cell cycle re-entry (CCR) induced by Aβ.	(106)
Tau KO mice (Dawson)		Subtle motor deficits at 12–15 months of age connected to mild dopaminergic deficits in Tau KO mice.	(107)
Tau KO mice (Dawson)		Tau-knockout mice develop age-dependent brain atrophy, iron accumulation and $\text{substantia nigra neuronal loss,}$ with concomitant cognitive deficits and parkinsonism.	(108)
Tau KO mice (Dawson) and mice expressing APP with the Swedish mutation Tau KO background		Overexpression of mutant APP in tau knockout mice, elicits the extensive $\text{formation of axonal spheroids}$ and more severe cognitive deficits.	(109)
Tau KO mice	Primary cultures of cortical neurons	A significantly lower LDH release, with a peak delayed by 24 h, was detected in Tau KO neurons after heat shock.	(110)
Tet/GSK3β mice on Tau KO (Dawson) background		The toxic effect of GSK3 overexpression is milder and slower in the absence of tau.	(111)
Tau KO mice (Dawson)		A deficit in migration of newborn cells in the subgranular zone was observed in Tau KO mice.	(112)
Tau KO mice	Primary cultures of hippocampal neurons	Tau-depleted neurons showed no signs of degeneration in the presence of Aβ.	(113)
Tau KO mice (Dawson)	Primary cultures of hippocampal neurons	Inhibition of neuronal maturation.	(114)
Tau KO mice (Harada)		Altered microtubule organization in small-caliber axons.	(115)

The following color code was used to assign results to the summary of GO-terms introduced in Figure 3: yellow: plasma membrane binding and function; red: apoptosis/cell death; purple: endo- and exocytosis; green: signaling mechanisms; blue: microtubule-dependent processes.