*4.2. ABCA7 in Brain Functions*

*Abca7* is mainly expressed by neurons and microglia in human and mouse brains [23,80–82]. Both isoforms described in Section 2.2 are observed by western blots in brain samples of healthy donors and AD patients [25]. Consequences of *Abca7* depletion

on brain cholesterol homeostasis were first investigated in mice. Lipidomic analysis of forebrain samples from five male *Abca7*−/<sup>−</sup> mice showed alterations in lipid content; of the 275 studied lipids, only 24 were significantly affected by the absence of expression of *Abca7* [83]. Among them, 12 subspecies in ethanolamine, three in phosphoglycerol, one in lysophosphatidylcholine, and two in shingomyelin were lower in brains of *Abca7*−/<sup>−</sup> mice. Three subspecies in phosphatidylcholine, one in ceramide, three in sulfatide, and one in cerebroside were increased, thus suggesting that *Abca7* deficiency may significantly affect cerebral lipid metabolism.

The same study reported deficiencies in spatial memory in *Abca7*−/<sup>−</sup> 20- to 22-monthold male and female mice [83] but these deficiencies were only observed in 19- to 20-weekold females in another study performed by Logge et al. [84]. In the same study, males and females displayed an altered novel object recognition but this was more pronounced in females [84]. No difference between genders or with wild type mice was measured when a battery of tests for behavior was realized. Indeed, *Abca7*−/<sup>−</sup> mice showed the same sensory abilities, neurological reflexes, motor functions, anxiety, spatial learning and shortterm memory as the wild-type mice [84]. No significant role in neurogenesis or neuron proliferation has been observed in another study in which only 8.5-month-old males were studied [85]. All these data suggest that ABCA7 might play a minor role in behavioral domains, but again further studies considering mouse strains, ages, sex or methodology are necessary to elucidate the role of ABCA7 in brain development and behaviors.

In humans, it was demonstrated more recently in brain samples that levels of ABCA7 modestly but significantly decrease with normal aging [23]. A significant association between ABCA7 SNP (rs3764650) and cognitive decline was only observed in females in a longitudinal study including 3267 females and 3026 males [70].
