Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

Abstract

BackgroundApolipoprotein 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.MethodsWe analyzed Arg‐61 apoE mice, a gene‐targeted model that selectively displays domain interaction.ResultsThe 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.ConclusionsDomain 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.

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

“…2, c and d, and 3, a-c). Furthermore, previous data seem to favor the loss of the excess proliferating cells via apoptosis since; even though some DCXpositive cells may retain their multipotentiality (74) and thus are likely to differentiate into glia, Zhong et al (18) reported that there was neither gliosis nor difference in NeuN-positive cell counts in the hippocampus of Arg-61 versus C57BL/6J mice. Meanwhile, the fact that we observed even a higher level of cleaved caspases-3 in older animals seems contrary to our earlier speculation about potential apoptosis of most of the mitotic DCX cells in young Arg-61 mice.…”

“…This cognitive deficit has been attributed, among other factors, to certain pathologies associated with early stage AD in human subjects, namely synaptic degeneration (43). This may be as a result of astrocyte dysfunctions in the Arg-61 mouse (18). However, it is worth pointing out that no deficit was found in 12-month-old Arg-61 mice during the training phase.…”

“…Furthermore, Michikawa and Yanagisawa,(77) demonstrated that apoptotic cell death in neurons induced by apoE4 may be as a result of reduced endogenous cholesterol secretion; interestingly, Arg-61 mice showed reduced cholesterol secretion (18). Thus, taken together with the 87% increase in cleaved caspase-3 and its role as the main executioner caspase in apoptosis (78), it is tempting to speculate that a higher percentage of the excess proliferating cells in the Arg-61 mice, as in normal conditions, become apoptotic or die at one point or another without becoming functional or getting integrated into the local circuit (79).…”

“…Arg-61 mice also showed cognitive deficits at 12 months (18), but no amyloidosis has been reported. Given that healthy apoE4 carriers show cognitive deficits and AD starts early in them, we hypothesize that the (negative) effect of apoE4 on cognition may be independent of old age or AD-like hallmark pathologies and that domain interaction may be sufficient to cause this age-independent, apoE4-induced cognitive deficits.…”

Long-Term Cognitive Correlates of Traumatic Brain Injury across Adulthood and Interactions with APOE Genotype, Sex, and Age Cohorts

“…While some studies suggest that APP plays a protective role post-TBI (Thornton, Vink, Blumbergs, & VanDen Heuvel, 2006), individuals with APOE ε4 + genotype experience increased post-injury Aβ deposition and reduced Aβ clearance (Hartman et al, 2002), which may in turn lead to an increased risk of Aβ plaque formation characteristic of dementia pathology. Compared to APOE ε3, the APOE ε4 isoform of the apolipoprotein E is also less able to repair synapses and protect neurons in the event of injury (Zhong, Scearce-Levie, Ramaswamy, & Weisgraber, 2008) (Katzman et al, 1996;Rohling et al, 2011;Sundstrom et al, 2007;Tang et al, 1996). The majority of these studies have included participants carrying the ε2 allele within the reference group despite evidence that ε2 may protect against degenerative neuropathology (Liu et al, 2013).…”