PMID- 27656027
OWN - NLM
STAT- MEDLINE
DCOM- 20170817
LR  - 20210421
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 36
IP  - 38
DP  - 2016 Sep 21
TI  - Reduced Efficacy of Anti-Abeta Immunotherapy in a Mouse Model of Amyloid Deposition 
      and Vascular Cognitive Impairment Comorbidity.
PG  - 9896-907
LID - 10.1523/JNEUROSCI.1762-16.2016 [doi]
AB  - Vascular cognitive impairment and dementia (VCID) is the second most common form 
      of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD 
      patients also have some form of VCID. One promising therapeutic for AD is anti-Abeta 
      immunotherapy, which uses antibodies against Abeta to clear it from the brain. While 
      successful in clearing Abeta and improving cognition in mice, anti-Abeta immunotherapy 
      failed to reach primary cognitive outcomes in several different clinical trials. 
      We hypothesized that one potential reason the anti-Abeta immunotherapy clinical 
      trials were unsuccessful was due to this high percentage of VCID comorbidity in 
      the AD population. We used our unique model of VCID-amyloid comorbidity to test 
      this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a 
      control diet or a diet that induces hyperhomocysteinemia (HHcy). After being 
      placed on the diet for 3 months, the mice then received intraperotineal 
      injections of either IgG2a control or 3D6 for another 3 months. While we found 
      that treatment of our comorbidity model with 3D6 resulted in decreased total Abeta 
      levels, there was no cognitive benefit of the anti-Abeta immunotherapy in our 
      AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the 
      APP/PS1/control but further increased in an additive fashion when 3D6 was 
      administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Abeta 
      immunotherapy in patients with both AD and VCID would be ineffective on cognitive 
      outcomes. SIGNIFICANCE STATEMENT: Despite significant mouse model data 
      demonstrating both pathological and cognitive efficacy of anti-Abeta immunotherapy 
      for the treatment of Alzheimer's disease, clinical trial outcomes have been 
      underwhelming, failing to meet any primary endpoints. We show here that vascular 
      cognitive impairment and dementia (VCID) comorbidity eliminates cognitive 
      efficacy of anti-Abeta immunotherapy, despite amyloid clearance. Further, 
      cerebrovascular adverse events of the anti-Abeta immunotherapy are significantly 
      exacerbated by the VCID comorbidity. These data suggest that VCID comorbidity 
      with Alzheimer's disease may mute the response to anti-Abeta immunotherapy.
CI  - Copyright (c) 2016 the authors 0270-6474/16/369896-12$15.00/0.
FAU - Weekman, Erica M
AU  - Weekman EM
AD  - Sanders-Brown Center on Aging, Department of Physiology.
FAU - Sudduth, Tiffany L
AU  - Sudduth TL
AD  - Sanders-Brown Center on Aging, Department of Physiology.
FAU - Caverly, Carly N
AU  - Caverly CN
AD  - Sanders-Brown Center on Aging, Department of Physiology.
FAU - Kopper, Timothy J
AU  - Kopper TJ
AD  - Department of Physiology.
FAU - Phillips, Oliver W
AU  - Phillips OW
AUID- ORCID: 0000-0003-0387-2878
AD  - Sanders-Brown Center on Aging, Department of Physiology.
FAU - Powell, Dave K
AU  - Powell DK
AD  - Magnetic Resonance Imaging and Spectroscopy Center, Department of Biomedical 
      Engineering, University of Kentucky, Lexington, Kentucky 40536.
FAU - Wilcock, Donna M
AU  - Wilcock DM
AD  - Sanders-Brown Center on Aging, Department of Physiology, donna.wilcock@uky.edu.
LA  - eng
GR  - F31 NS092202/NS/NINDS NIH HHS/United States
GR  - R01 NS079637/NS/NINDS NIH HHS/United States
GR  - R01 NS097722/NS/NINDS NIH HHS/United States
GR  - S10 RR029541/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (CD11b Antigen)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Presenilin-1)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Amyloid beta-Peptides/*immunology
MH  - Amyloid beta-Protein Precursor/genetics/metabolism
MH  - Animals
MH  - CD11b Antigen/metabolism
MH  - *Dementia, Vascular/complications/diagnostic imaging/genetics/therapy
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Hyperhomocysteinemia/complications/etiology/genetics/therapy
MH  - Immunotherapy/*methods
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Maze Learning
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Presenilin-1/genetics/metabolism
MH  - RNA, Messenger/metabolism
PMC - PMC5030351
OTO - NOTNLM
OT  - amyloid
OT  - immunotherapy
OT  - microglia
OT  - microhemorrhage
OT  - mixed dementia
OT  - vascular cognitive impairment
EDAT- 2016/09/23 06:00
MHDA- 2017/08/18 06:00
PMCR- 2017/03/21
CRDT- 2016/09/23 06:00
PHST- 2016/06/01 00:00 [received]
PHST- 2016/08/09 00:00 [accepted]
PHST- 2016/09/23 06:00 [entrez]
PHST- 2016/09/23 06:00 [pubmed]
PHST- 2017/08/18 06:00 [medline]
PHST- 2017/03/21 00:00 [pmc-release]
AID - 36/38/9896 [pii]
AID - 1762-16 [pii]
AID - 10.1523/JNEUROSCI.1762-16.2016 [doi]
PST - ppublish
SO  - J Neurosci. 2016 Sep 21;36(38):9896-907. doi: 10.1523/JNEUROSCI.1762-16.2016.