PMID- 35241183
OWN - NLM
STAT- MEDLINE
DCOM- 20220420
LR  - 20220517
IS  - 2051-5960 (Electronic)
IS  - 2051-5960 (Linking)
VI  - 10
IP  - 1
DP  - 2022 Mar 3
TI  - Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated 
      with elevated phosphorylated 3R/4R tau aggregation.
PG  - 27
LID - 10.1186/s40478-022-01330-x [doi]
LID - 27
AB  - Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by 
      mutations in the TSC1 and TSC2 genes and autosomal dominantly inherited. These 
      mutations cause hyperactivation of the mammalian Target of Rapamycin (mTOR) 
      pathway, leading to the development of nonmalignant masses involving various 
      organ systems. Patients with TSC also experience neuropsychiatric symptoms 
      collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric 
      Disorder (TAND). Due to research advancements in TSC, patients now live well 
      beyond the age of 50. Many experience objective impairment of memory and 
      executive function, supported by formal neuropsychological testing, beginning in 
      their late 40s. Biomarker analysis has described elevated levels of 
      phosphorylated tau-181 in the cerebrospinal fluid of patients with TAND. Tau-PET 
      imaging has also shown focal accumulation of the radiotracer flortaucipir 
      (AV1451), suggesting that TSC may be a neurodegenerative disorder arising from 
      accumulation of phosphorylated tau. However, the flortaucipir tracer has been 
      reported to have significant off-target binding, preventing definitive 
      conclusions from being drawn about the molecular etiology of neurodegeneration in 
      TSC. Therefore, we initiated the Colocalization of AV1451 and Phosphorylated Tau 
      in Adult brain tissue (CAPA) study. This study aimed to determine if flortaucipir 
      is bound to phosphorylated tau in brains of patients with TSC and further sought 
      to determine the specific tau isoform seen in TSC. Our results show that 
      flortaucipir labels the 3R/4R isoform of phosphorylated tau, commonly seen in 
      Alzheimer's disease. However, amyloid staining was negative in brains of adult 
      patients with TSC. Therefore, we conclude that TAND symptoms are due to the 
      accumulation of the phosphorylated tau isoform seen in Alzheimer's disease. This 
      study suggests that hyperactivation of the mammalian Target of Rapamycin pathway 
      may play a role in the amyloid-independent development of 3R/4R tau aggregation. 
      Our findings could lead to a new era of anti-tau therapies used to treat both 
      disorders.
CI  - (c) 2022. The Author(s).
FAU - Liu, Andy J
AU  - Liu AJ
AUID- ORCID: 0000-0003-3096-1788
AD  - Duke University, 932 Morreene Rd, Durham, NC, USA. Andy.liu@duke.edu.
FAU - Lusk, Jay B
AU  - Lusk JB
AD  - Duke University, 932 Morreene Rd, Durham, NC, USA.
FAU - Ervin, John
AU  - Ervin J
AD  - Duke University, 932 Morreene Rd, Durham, NC, USA.
FAU - Burke, James
AU  - Burke J
AD  - Duke University, 932 Morreene Rd, Durham, NC, USA.
FAU - O'Brien, Richard
AU  - O'Brien R
AD  - Duke University, 932 Morreene Rd, Durham, NC, USA.
FAU - Wang, Shih-Hsiu J
AU  - Wang SJ
AD  - Duke University, 932 Morreene Rd, Durham, NC, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220303
PL  - England
TA  - Acta Neuropathol Commun
JT  - Acta neuropathologica communications
JID - 101610673
RN  - 0 (Amyloidogenic Proteins)
RN  - 0 (Protein Isoforms)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - *Alzheimer Disease/pathology
MH  - Amyloidogenic Proteins
MH  - *Amyloidosis
MH  - Humans
MH  - Protein Isoforms/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Tauopathies/metabolism
MH  - *Tuberous Sclerosis/complications/genetics/pathology
PMC - PMC8896101
OTO - NOTNLM
OT  - 3R tauopathy
OT  - 4R tauopathy
OT  - Alzheimer's disease
OT  - Phosphorylated tau
OT  - Tauopathy
OT  - Tuberous Sclerosis Complex
COIS- The authors declare that they have no competing interests.
EDAT- 2022/03/05 06:00
MHDA- 2022/04/21 06:00
PMCR- 2022/03/03
CRDT- 2022/03/04 05:34
PHST- 2022/02/09 00:00 [received]
PHST- 2022/02/11 00:00 [accepted]
PHST- 2022/03/04 05:34 [entrez]
PHST- 2022/03/05 06:00 [pubmed]
PHST- 2022/04/21 06:00 [medline]
PHST- 2022/03/03 00:00 [pmc-release]
AID - 10.1186/s40478-022-01330-x [pii]
AID - 1330 [pii]
AID - 10.1186/s40478-022-01330-x [doi]
PST - epublish
SO  - Acta Neuropathol Commun. 2022 Mar 3;10(1):27. doi: 10.1186/s40478-022-01330-x.