TY - JOUR
T1 - Sowing the Seeds of Discovery
T2 - Tau-Propagation Models of Alzheimer's Disease
AU - Bell, Benjamin J.
AU - Malvankar, Medhinee M.
AU - Tallon, Carolyn
AU - Slusher, Barbara S.
N1 - Funding Information:
ADDF-T-PEP-18-579974C; NIH/NIA-R01 AG059799; B.J.B. is funded by NRSA T32-5T32MH015330-41.
PY - 2020/11/4
Y1 - 2020/11/4
N2 - The propagation of pathological proteins throughout the brain is the primary physiological hallmark of the progression of Alzheimer's Disease (AD). A growing body of evidence indicates that hyperphosphorylated Tau proteins are spread transcellularly between neurons in a prionlike fashion, inducing misfolding and aggregation into neurofibrillary tangles which accumulate along specific connectivity pathways. Earlier transgenic rodent AD models did not capture this disease-relevant spread, and therefore, seeded Tau-propagation models have been developed. Here, mutant human Tau (as isolated protein or packaged into an adeno-associated virus (AAV) viral vector) is stereotaxically injected into select brain regions and its histopathological propagation to downstream neurons quantified. These models offer a faster and more direct mechanism to evaluate genetic components and therapeutic approaches which attenuate Tau spreading in vivo. Recently, these Tau-seeding models have revealed several new targets for AD drug discovery, including nSMase2, SIRT1, p300/CBP, LRP1, and TYROBP, as well as the potential therapeutics based on melatonin and chondroitinase ABC. Importantly, these Tau-propagation rodent models more closely phenocopy the progression of AD in humans and are therefore likely to improve preclinical studies and derisk future moves into clinical trials.
AB - The propagation of pathological proteins throughout the brain is the primary physiological hallmark of the progression of Alzheimer's Disease (AD). A growing body of evidence indicates that hyperphosphorylated Tau proteins are spread transcellularly between neurons in a prionlike fashion, inducing misfolding and aggregation into neurofibrillary tangles which accumulate along specific connectivity pathways. Earlier transgenic rodent AD models did not capture this disease-relevant spread, and therefore, seeded Tau-propagation models have been developed. Here, mutant human Tau (as isolated protein or packaged into an adeno-associated virus (AAV) viral vector) is stereotaxically injected into select brain regions and its histopathological propagation to downstream neurons quantified. These models offer a faster and more direct mechanism to evaluate genetic components and therapeutic approaches which attenuate Tau spreading in vivo. Recently, these Tau-seeding models have revealed several new targets for AD drug discovery, including nSMase2, SIRT1, p300/CBP, LRP1, and TYROBP, as well as the potential therapeutics based on melatonin and chondroitinase ABC. Importantly, these Tau-propagation rodent models more closely phenocopy the progression of AD in humans and are therefore likely to improve preclinical studies and derisk future moves into clinical trials.
KW - Alzheimer's disease
KW - SIRT1
KW - TYROBP
KW - Tau propagation
KW - Tau seeding
KW - extracellular vesicles
KW - melatonin
KW - nSMase2
KW - p300/CBP
UR - http://www.scopus.com/inward/record.url?scp=85094881781&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85094881781&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.0c00531
DO - 10.1021/acschemneuro.0c00531
M3 - Review article
C2 - 33050700
AN - SCOPUS:85094881781
VL - 11
SP - 3499
EP - 3509
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 21
ER -