Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice.
Alzheimer's disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One unresolved question in ApoE biology is whether ApoE is necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function. To bypass the effect of ApoE loss on plasma lipids, we generated a novel mouse model that expresses ApoE normally in peripheral tissues, but has severely reduced ApoE in the brain, allowing us to study brain ApoE loss in the context of a normal plasma lipid profile. We found that these brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction similar to that of ApoE KO mice; however, the bEKO mice did not have the learning and memory impairment observed in ApoE KO mice. Moreover, we found that the memory deficit in the ApoE KO mice was specific to female mice and was fully rescued in female bEKO mice. Furthermore, while the AMPA/NMDA ratio was reduced in ApoE KO mice, it was unchanged in bEKO mice compared with controls. These findings suggest that plasma lipid levels can influence cognition and synaptic function independent of ApoE expression in the brain.



One proposed treatment strategy for Alzheimer's disease (AD) is the reduction of ApoE, whose ε4 isoform is the most common genetic risk factor for the disease. A major concern of this strategy is that an animal model of ApoE deficiency, the ApoE knock-out (KO) mouse, has reduced synapses and cognitive impairment; however, these mice also develop dyslipidemia and severe atherosclerosis. Here, we have shown that genetic restoration of plasma ApoE to wild-type levels normalizes plasma lipids in ApoE KO mice. While this does not rescue synaptic loss, it does completely restore learning and memory in the mice, suggesting that both CNS and plasma ApoE are independent parameters that affect brain health.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Joachim.herz@utsouthwestern.edu Courtney.Lane@utsouthwestern.edu.
Courtney
C
Lane-Donovan
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Wen Mai
WM
Wong
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Murat S
0000-0003-4483-8166
MS
Durakoglugil
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Catherine R
0000-0001-6396-0146
CR
Wasser
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Shan
S
Jiang
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Xunde
0000-0003-3059-1254
X
Xian
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and Center for Neuroscience, Department of Neuroanatomy, Albert-Ludwigs-University, 79085 Freiburg, Germany Joachim.herz@utsouthwestern.edu Courtney.Lane@utsouthwestern.edu.
Joachim
J
Herz
D000818:Animals; D001057:Apolipoproteins E / Q000097:blood* / Q000235:genetics*; D003071:Cognition; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D008055:Lipids / Q000097:blood*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
D001057:Apolipoproteins E; D008055:Lipids
Alzheimer's; ApoE; ApoE4; cognition; dementia
Hum Mol Genet. 2000 Feb 12;9(3):353-61
10655544
Brain Res. 1997 Mar 21;751(2):307-14
9099820
Atherosclerosis. 1999 Aug;145(2):301-8
10488957
Arch Neurol. 2004 Aug;61(8):1200-5
15313836
Eur J Neurosci. 2000 Dec;12(12):4541-6
11122365
Science. 1992 Oct 16;258(5081):468-71
1411543
Ann Neurol. 2014 Apr;75(4):563-73
24623176
Cell. 1992 Oct 16;71(2):343-53
1423598
Neuron. 2014 Aug 20;83(4):771-87
25144875
Exp Neurol. 1997 Feb;143(2):313-8
9056393
Mol Chem Neuropathol. 1996 May-Aug;28(1-3):97-103
8871947
Am J Physiol Cell Physiol. 2007 Apr;292(4):C1256-62
16870825
Behav Brain Res. 2015 Feb 1;278:356-9
25453744
J Clin Invest. 1986 Nov;78(5):1206-19
3771793
Neurology. 1992 Jan;42(1):115-9
1734291
Exp Neurol. 2001 May;169(1):13-22
11312553
Nature. 2012 May 16;485(7399):512-6
22622580
EMBO Mol Med. 2016 Mar 31;8(4):328-45
26902204
J Am Heart Assoc. 2014 Nov 12;3(6):e001156
25392541
JAMA Neurol. 2014 Oct;71(10 ):1228-36
25111166
Lab Invest. 2001 Jul;81(7):953-60
11454984
Neuroscience. 1999;91(1):401-3
10336088
Sci Transl Med. 2011 Jun 29;3(89):89ra57
21715678
Annu Rev Nutr. 2012 Aug 21;32:147-60
22540257
J Lipid Res. 1998 Aug;39(8):1594-600
9717719
Neurosci Lett. 1995 Oct 13;199(1):1-4
8584214
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7
10694577
J Neurosci. 2011 Dec 7;31(49):18007-12
22159114
Free Radic Biol Med. 2002 Oct 15;33(8):1115-20
12374623
Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):12011-6
20547867
Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1807-16
23620513
Exp Neurol. 1995 Dec;136(2):107-22
7498401
Science. 2001 Nov 9;294(5545):1354-7
11701931
Neurosci Lett. 1998 May 22;248(1):21-4
9665654
Am J Geriatr Psychiatry. 2008 May;16(5):343-54
18448847
Am J Physiol Regul Integr Comp Physiol. 2012 Nov 1;303(9):R903-8
22933021
J Neurosci. 2014 Oct 15;34(42):13963-75
25319693
J Neurosci. 2008 Feb 6;28(6):1452-9
18256266
J Neurosci. 2014 May 21;34(21):7281-92
24849360
JAMA Neurol. 2014 Oct;71(10 ):1213-5
25110920
J Cereb Blood Flow Metab. 1998 Apr;18(4):361-6
9538900
Nutr Neurosci. 2014 Nov;17(6):241-51
24192577
Endocrinology. 2008 May;149(5):2628-36
18276751
J Cereb Blood Flow Metab. 2013 Jun;33(6):954-62
23486293
Nat Genet. 1994 Jun;7(2):180-4
7920638
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10914-9
9724804
J Biol Chem. 1997 Jul 18;272(29):17972-80
9218423
Cell Metab. 2007 Apr;5(4):279-91
17403372
Biochim Biophys Acta. 1987 Jan 13;917(1):148-61
3539206
J Lipid Res. 1996 Apr;37(4):693-707
8732771
Science. 1993 Aug 13;261(5123):921-3
8346443
Brain Res. 1999 Oct 2;843(1-2):87-94
10528114
Brain Res. 1990 Jan 8;506(2):249-53
2302565