Apolipoprotein E4 domain interaction: synaptic and cognitive deficits in mice.
BACKGROUND
Apolipoprotein E4 (apoE4), the major genetic risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases, has three structural and biophysical properties that distinguish it from the other isoforms-domain interaction, reduced stability, and lack of cysteine. Assessing their relative contributions to effects of apoE4-associated pathogenesis in AD is important from a mechanistic and therapeutic perspective, that is not possible using human apoE transgene or knock-in models.


METHODS
We analyzed Arg-61 apoE mice, a gene-targeted model that selectively displays domain interaction.


RESULTS
The mice displayed age-dependent loss of the synaptic protein synaptophysin in neocortex and hippocampus and had lower levels of the postsynaptic neuroligin-1. Activation of dentate gyrus granule neurons increased Arc expression 3.5-fold in wildtype mice but only 2.3-fold in Arg-61 mice. The losses of synaptic proteins caused a mild memory deficit in Arg-61 mice in the water-maze test. Since synaptic integrity requires efficient glutamate uptake, we measured astrocyte glutamate transporter 1 in the hippocampus. The level was reduced in Arg-61 mice, suggesting that inefficient glutamate uptake by astrocytes causes chronic excitotoxicity. Consistent with the reduced secretion of Arg-61 apoE by astrocytes in this model, cholesterol secretion was also reduced 34%. This reduction could also contribute to the synaptic deficits by limiting the availability of cholesterol for neuronal repair.


CONCLUSIONS
Domain interaction in the absence of other structural characteristics of apoE4 is sufficient to cause synaptic pathology and functional synaptic deficits, potentially associated with astrocyte dysfunction and impaired maintenance of neurons. Therapeutic targeting of domain interaction might blunt effects of apoE4 in neurodegenerative disease.
Zhong
Ning
N
Gladstone Institute of Neurological Disease, The J. David Gladstone Institutes, San Francisco, CA, USA.
Scearce-Levie
Kimberly
K
Ramaswamy
Gayathri
G
Weisgraber
Karl H
KH
D000818:Animals; D053327:Apolipoprotein E4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D016708:Synaptophysin / Q000378:metabolism
D053327:Apolipoprotein E4; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos; D016708:Synaptophysin; C092069:activity regulated cytoskeletal-associated protein