A brief overview of tauopathy: causes, consequences, and therapeutic strategies
Miranda Orr, A Campbell Sullivan, Bess Frost
University of Texas Health San Antonio
Trends Pharmacol Sci 2017 July 38(7) 637-648
1975 Weingarten et al. id protein co purify with microtubules, req'd for microtubule stability
key component of NFTs 1988: Goedert et al PNAS 85(11), and Wischik et al PNAS 85(12)
neuroimaging:
- MRI -
- changes in both gray and white matter
- AD have hippocampal and parietal atrophy
- PSP have atrophy of midbrain
- CBS have changes of basal ganglia and bilateral frontal lobes
- PET - radioactive tracer of brain function
Treatment:
- Cholinesterase inhibitors
- NMDA receptor antagonist
Pathogenic tau:
- aberrant phosphorylation (Morishima-Kawashima 1995, Hanger 1998, Mair 2016)
- other PTMs (Wang 2016)
- truncation (Wischik 1988)
- aggregation into oligomers and insoluble filaments (Holtzman 2016)
induced by amyloid beta and alpha synuclein (not reviewed here)
Diagnostic:
total tau in CSF and plasma, and total phosphotau in plasma are strongly associated with AD and MCI due to AD
tau PET allows differentiation of pathogenic tau distribution within the brain
plasma-isolated exosomal tau Goetzl FasebJ 2016 30(11)
Study of Nasal Insulin in the Fight against Forgetfulness (SNIFF)
pathogenic tau promotes filamentous actin stabilization and formation of filamentous actin bundles [99Fulga TA, et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal
degeneration in vivo. Nat Cell Biol. 2007; 9(2):139–48. ]
this impacts mitochondrial dynamics, leading to oxidative stress [100DuBoff B, et al. Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron.
2012; 75(4):618–32]
this also impacts nuclear envelope that involutes, disrupting nucleoskeleton, causing constitutive heterochromatin to relax and allows genes normally silent to transcribe [101Frost B, et al. Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Curr Biol. 2016;
26(1):129–36, 102Frost B, et al. Tau promotes neurodegeneration through global chromatin relaxation. Nat
Neurosci. 2014; 17(3):357–66]
synaptic loss/dysfunction, impaired axonal transport, and microtubule destabilization have been reviewed elsewhere [12Arendt T, et al. Tau and tauopathies. Brain Res Bull. 2016; 126(Pt 3):238–292. , 110Frost B, et al. Connecting the dots between tau dysfunction and neurodegeneration. Trends Cell
Biol. 2015; 25(1):46–53]
