Apolipoprotein E4 causes early olfactory network abnormalities and short-term olfactory memory impairments

Abstract

While apolipoprotein (Apo)E4 is linked to increased incidence of Alzheimer’s disease (AD), there is growing evidence that it plays a role in functional brain irregularities that are independent of AD pathology. However, ApoE4-driven functional differences within olfactory processing regions have yet to be examined. Utilizing knock-in mice humanized to ApoE4 versus the more common ApoE3, we examined a simple olfactory perceptual memory that relies on the transfer of information from the olfactory bulb (OB) to the piriform cortex (PCX), the primary cortical region involved in higher order olfaction. In addition, we have recorded in vivo resting and odor-evoked local field potentials (LPF) from both brain regions and measured corresponding odor response magnitudes in anesthetized young (6-month-old) and middle-aged (12-month-old) ApoE mice. Young ApoE4 compared to ApoE3 mice exhibited a behavioral olfactory deficit coinciding with hyperactive odor-evoked response magnitudes within the OB that were not observed in older ApoE4 mice. Meanwhile, middle-aged ApoE4 compared to ApoE3 mice exhibited heightened response magnitudes in the PCX without a corresponding olfactory deficit, suggesting a shift with aging in ApoE4-driven effects from OB to PCX. Interestingly, the increased ApoE4-specific response in the PCX at middle-age was primarily due to a dampening of baseline spontaneous activity rather than an increase in evoked response power. Our findings indicate that early ApoE4-driven olfactory memory impairments and OB network abnormalities may be a precursor to later network dysfunction in the PCX, a region that not only is targeted early in AD, but may be selectively vulnerable to ApoE4 genotype.

Apolipoprotein E regulates the maturation of injury-induced adult-born hippocampal neurons following traumatic brain injury

“…Together, these previous findings may help to explain the cognitive impairments exhibited by mice lacking ApoE or expressing ApoE4 particularly in spatial learning/memory and in olfactory memory, two neurogenic-dependent behaviors [63][64][65][66][67][68][69][70][71]. Although it remains unclear whether recovery from injuries such as TBI is dependent on neurogenesis in general and ApoE state in particular, the present study adds needed insight into a potential mechanism linking the two.…”

Odor identification as a biomarker of preclinical AD in older adults at risk

“…These modifications appear to precede later functional differences and increasing structural abnormality in brain regions related to olfaction. 27 …”

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

“…Multiple mechanisms appear to drive the pathogenic effects of the APOE4 allele in the brain, including enhancing Aβ deposition while reducing Aβ clearance and degradation; modulating synaptic integrity; modulating cholesterol levels in the brain and the availability of cholesterol and other lipids to neurons; and inducing changes in reactive O 2 scavenging in the CNS Ma et al, 1994;Bales et al, 1997;Higgins et al, 1997;Haan et al, 1999;Holtzman et al, 2000;Shibata et al, 2000;Bu, 2009;Kim et al, 2009;Kolovou et al, 2009;Andrews-Zwilling et al, 2010;Verghese et al, 2011;Villemagne et al, 2011;Leung et al, 2012;Mahley and Huang, 2012;Andrews et al, 2013;Liu et al, 2013;Reinvang et al, 2013;Zlokovic, 2013;Rodriguez et al, 2014). In the absence of a dementia diagnosis, human APOE4-carriers still display structural and functional differences within regions of the hippocampus and cortex, and cognitive decline compared to age-matched non-carriers (Bookheimer and Burggren, 2009;Filippini et al, 2009;Olofsson et al, 2010;Sheline et al, 2010;Wisdom et al, 2011;Liu et al, 2013;Di Battista et al, 2016), and mouse models show cognitive deficits linked to APOE4 expression without AD pathology (Leung et al, 2012;Peng et al, 2017;East et al, 2018).…”