Table 1.
Adverse effects of lowering tau
| Role | Experimental paradigm | Adverse effects | References |
|---|---|---|---|
|
Microtubules Regulation of microtubule dynamics |
Tau knockdown | ↓ In labile microtubule mass, ↑ in the stable domain | Qiang et al. [213] |
| Tau knockdown | ↓ Neuronal outgrowth | Liu et al. [150] | |
| Tau knockdown | Impaired repulsive response of the growth cone | Biswas and Kalil, [22], Li et al. [147] | |
| Tau knockdown | Disruption to axonal extension | Caceres and Kosik [36] | |
| Tau knockdown/ knockout | Delayed neuronal maturation | Caceres et al. [37], Dawson et al. [54] | |
| Tau knockout | ↓ Microtubule density in small caliber axons | Harada et al. [96] | |
| No tau added to microtubules in vitro (compared to tau presence) | ↑ EB1 binding to microtubule ends, ↑ catastrophe frequency | Ramirez-Rios et al. [217] | |
| Regulation of axonal transport | 4R tau knockdown | ↑ Velocity of mitochondrial axonal transport | Beevers et al. [15] |
| Protection of microtubules from cleavage | Tau knockdown | Katanin-mediated cleavage, loss of microtubules and ↓ axon length | Qiang et al. [214] |
| Tau knockdown | ↑ Neuronal branching | Yu et al. [287] | |
|
Synaptic Activity LTP, LTD and memory |
Tau knockout | Age-dependent cognitive deficits in contextual fear conditioning, Y-maze, Morris Water Maze and reversal learning tests | Ahmed et al. [3], Lei et al. [146], Ma et al. [164], Regan et al. [218] |
| Tau knockout | Severe LTP deficit | Ahmed et al. [3] | |
| Tau knockout | LTD deficits | Kimura et al. [128], Regan et al. [218] | |
| Acute tau knockdown using shRNA | ↓ Dendritic spine density, loss of synaptic proteins and significant spatial memory impairments (no compensatory MAP upregulation) | Velazquez et al. [266] | |
| Regulation of neuronal hyperexcitability | Tau knockout | Hyperpolarised neuronal membrane potential | Pallas‐Bazarra et al. [197] |
| Tau knockout | Impaired basal neurotransmission when crossed with APP transgenic mouse | Puzzo et al. [209] | |
| Neurogenesis and synaptogenesis | Acute tau knockdown using shRNA | ↓ In baseline spine numbers, pro-synaptic response to BDNF blocked | Chen et al. [44] |
| Acute tau knockdown using shRNA | ↓ Apical and basal dendrite density | Velazquez et al. [266] | |
| Tau knockout | Failed normal migration of new-born granule neurons in the dentate gyrus | Fuster-Matanzo et al. [78], Sapir et al. [227] | |
| Tau knockout | ↓ Dendritic length, disrupted PSD and mossy fiber terminal formation | Pallas‐Bazarra et al. [197] | |
| Tau knockout | Impaired neurogenesis | Hong et al. [107] | |
| Tau knockout | Delayed neuronal maturation | Dawson et al. [54] | |
| Tau knockout | Transcriptional repression of neuronal genes | de Barreda et al. [11] | |
|
Behaviour Hyperactivity |
Tau knockout | Hyperactivity | Biundo et al. [23], Ikegami et al. [114] |
| Anxiety | Tau knockout | ↑ Rearing behaviour | Lei et al. [146] |
| Tau knockout | ↑ Anxiety in open field arenas | Gonçalves et al. [86] | |
| Sleep | Tau knockout | ↑ Wakefulness and disruption to normal circadian activities | Arnes et al. [8], Cantero et al. [41] |
| Motor function | Tau knockout | FTD-P17-like motor dysfunction | Lei et al. [145] |
| Tau knockout | Changes in gait, ↓ locomotion and muscle weakness | Lei et al. [145, 146], Ikegami et al. [114] | |
| Tau knockout | Loss of dopaminergic neurons | Lei et al. [145], Ma et al. [164] | |
| Tau knockout, tau 4R knockout, acute tau knockdown using shRNA | Significant impairment in balance beam or rotarod performance | Lei et al. [145, 146], Morris et al. [186], Lopes et al. [157],Ikegami et al. [114],Ma et al. [164],Gumucio et al. [93], Velazquez et al. [266] | |
|
Myelination Regulation of myelination |
Tau knockdown using siRNA | ↓ Oligodendrocyte process outgrowth, ↓ myelin basic protein expression, ↓contact with axons | Seiberlich et al. [230] |
| Tau knockdown using siRNA | ↓ Recovery after sciatic nerve damage, defective myelin debris clearance, impaired Schwann cell migration and differentiation | Yi et al. [285] | |
| Tau knockout | Age-dependent degeneration of myelinated fibers, ↓ nerve conduction and progressive hypomyelination, resulting in motor and nociceptive impairments | Lopes et al. [157], Sotiropoulos et al. [237] | |
| Tau knockout | Worse clinical outcome after experimental autoimmune encephalomyelitis (EAE) | Weinger et al. [277] | |
| Expression of an inducible, truncated tau | Demyelination and development of gait abnormalities | LoPresti [160] | |
|
Response to injury Promotion of recovery |
Tau knockout | ↓ Recovery after sciatic nerve damage | Yi et al. [285][] |
| Tau knockout | Worse outcome after EAE | Weinger et al. [277] | |
|
Mitochondrial activity Mitochondrial mobility and health |
Tau knockdown | ↓ Mitochondrial mobility and ↑ number of abnormal mitochondria | Sapir et al. [227] |
|
Iron Regulation of iron homeostasis |
Tau knockout | Age-dependent iron accumulation associated with neurodegeneration, cognitive deficits and parkinsonian-like motor deficits, deficits rescued by treatment with the iron chelator clioquinol | Lei et al. [144, 145] |
| Lithium-mediated tau reduction | ↑ Iron accumulation in the brain, ↓ cellular efflux of iron | Lei et al. [143] | |
|
Nuclear activity Protection of DNA from damage |
Tau knockout | Extensive heat shock damage (DNA breaks) in neurons | Sultan et al. [246] |
| Tau knockout | ↑ DNA fragmentation under physiological conditions and high susceptibility to DNA breakage after hyperthermic stress | Violet et al. [267] | |
| Tau knockout | Delayed repair of double-strand breaks after heat shock | Violet et al. [267] | |
| Maintenance of chromosomal stability | Knockout of one or both copies of tau | Marked ↑ in aneuploidy | Granic et al. [88], Rossi et al. [222] |
| Tau knockout | Disrupted pericentromeric heterochromatin | Maina et al. [165], Mansuroglu et al. [169] | |
| Regulation of transcription | Tau knockdown using shRNA | ↓ mRNA and protein levels of VGLUT1 | Siano et al. [234] |
| Tau knockout | Upregulation of proteins such as BAF-57 (involved in neuron-specific gene repression) | de Barreda et al. [11] | |
| Tau knockdown | rDNA transcription altered | Maina et al. [165], Samra et al. [226] | |
| Tumour suppression | Tau knockdown | Enhanced cell growth and invasion in clear cell renal cell carcinoma | Han et al. [95] |
| Glucose metabolism | Tau knockout | Insulin resistance in the hippocampus | Marciniak et al. [170] |
| Tau knockout | Pancreatic β cell dysfunction and glucose intolerance | Wijesekara et al. [279] |
Summary of studies reporting adverse outcomes after lowering tau in a range of experimental systems