PMID- 38358083
OWN - NLM
STAT- Publisher
LR  - 20240515
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Linking)
DP  - 2024 Feb 15
TI  - Homocysteine potentiates amyloid beta -induced death receptor 4- and 5-mediated 
      cerebral endothelial cell apoptosis, blood brain barrier dysfunction and 
      angiogenic impairment.
PG  - e14106
LID - 10.1111/acel.14106 [doi]
AB  - Cerebrovascular dysfunction has been implicated as a major contributor to 
      Alzheimer's Disease (AD) pathology, with cerebral endothelial cell (cEC) stress 
      promoting ischemia, cerebral-blood flow impairments and blood-brain barrier (BBB) 
      permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular 
      risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and 
      risk. Yet, the underlying molecular mechanisms for this interaction remain 
      unclear. Our lab has demonstrated that amyloid beta 40 (Abeta40) species, and 
      particularly Abeta40-E22Q (AbetaQ22; vasculotropic Dutch mutant), promote death 
      receptor 4 and 5 (DR4/DR5)-mediated apoptosis in human cECs, barrier 
      permeability, and angiogenic impairment. Previous studies show that Hhcy also 
      induces EC dysfunction, but it remains unknown whether Abeta and homocysteine 
      function through common molecular mechanisms. We tested the hypotheses that Hhcy 
      exacerbates Abeta-induced cEC DR4/5-mediated apoptosis, barrier dysfunction, and 
      angiogenesis defects. This study was the first to demonstrate that Hhcy 
      specifically potentiates AbetaQ22-mediated activation of the DR4/5-mediated 
      extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 
      activation, cytochrome-c release and DNA fragmentation. Additionally, we revealed 
      that Hhcy intensifies the deregulation of the same cEC junction proteins mediated 
      by Abeta, precipitating BBB permeability. Furthermore, Hhcy and AbetaQ22, impairing 
      VEGF-A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC 
      angiogenic capabilities. Overall, these results show that the presence of the CV 
      risk factor Hhcy exacerbates Abeta-induced cEC apoptosis, barrier dysfunction, and 
      angiogenic impairment. This study reveals specific mechanisms through which 
      amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, 
      highlighting new potential molecular targets against vascular pathology in 
      comorbid AD/CAA and Hhcy conditions.
CI  - (c) 2024 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Carey, Ashley
AU  - Carey A
AD  - Department of Neural Sciences, Alzheimer's Center at Temple, Temple University 
      Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
FAU - Parodi-Rullan, Rebecca
AU  - Parodi-Rullan R
AUID- ORCID: 0000-0002-0466-1047
AD  - Department of Neural Sciences, Alzheimer's Center at Temple, Temple University 
      Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
FAU - Vazquez-Torres, Rafael
AU  - Vazquez-Torres R
AD  - Department of Neural Sciences, Alzheimer's Center at Temple, Temple University 
      Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
FAU - Canepa, Elisa
AU  - Canepa E
AD  - Department of Neural Sciences, Alzheimer's Center at Temple, Temple University 
      Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
FAU - Fossati, Silvia
AU  - Fossati S
AUID- ORCID: 0000-0002-2047-222X
AD  - Department of Neural Sciences, Alzheimer's Center at Temple, Temple University 
      Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA.
LA  - eng
GR  - R01 AG062572/AG/NIA NIH HHS/United States
GR  - R01 NS104127/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20240215
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
SB  - IM
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - amyloid beta
OT  - angiogenesis
OT  - apoptosis
OT  - blood brain barrier
OT  - cardiovascular risk
OT  - cerebral amyloid angiopathy
OT  - cerebrovascular dysfunction
OT  - endothelial cells
OT  - hyperhomocysteinemia
EDAT- 2024/02/15 12:43
MHDA- 2024/02/15 12:43
CRDT- 2024/02/15 08:28
PHST- 2024/01/10 00:00 [revised]
PHST- 2023/12/05 00:00 [received]
PHST- 2024/01/17 00:00 [accepted]
PHST- 2024/02/15 12:43 [medline]
PHST- 2024/02/15 12:43 [pubmed]
PHST- 2024/02/15 08:28 [entrez]
AID - 10.1111/acel.14106 [doi]
PST - aheadofprint
SO  - Aging Cell. 2024 Feb 15:e14106. doi: 10.1111/acel.14106.