A comparative study of the time courses of Aβ42, Aβ40, and ApoE deposition in relation to astrogliosis in Tg2576 suggested that Aβ42 preceded ApoE in the plaque, followed by Aβ40, which occupied the center of the deposit in later stages. Moreover, the presence of ApoE was correlated with the astrogliosis [
297]. The Aβ deposits were compared in
heterozygous V717F APP Tg mice (APP
V717F+/−) with graded expression of the mouse ApoE gene. The mice carried no (ApoE −/−), one (ApoE +/−) or two (ApoE +/+) alleles. Amyloid deposits as well as Aβ immunoreactivity were lacking in the cortex in the absence of ApoE expression in animals aged 22 months. Aβ deposition was observed—although at a lower level than in the ApoE +/+ mice—when only one allele (ApoE +/−) was present. ApoE immunoreactivity was found in all of the thioflavin S positive amyloid cores in the Tg mice with one or two ApoE alleles [
15]. In a later study with
homozygous V717F APP Tg mice (APP
V717F+/+) on an ApoE null background, it was found that the cortical and dentate gyrus deposition of Aβ was dramatically reduced, but that the densities of the CA1 and CA3 diffuse deposits were increased even when there was no thioflavin S positive deposits [
144]. The overexpression of ApoE4 in a hAPP mouse, knocked out for ApoE, increases the number of focal, amyloid deposits tenfold in comparison with the ApoE3 mice [
133]. Since the dystrophic neurites that are found in the coronae of the plaques are only observed when the deposit is focal with amyloid, it is no wonder that no “neuritic plaques” are found in the ApoE −/− mice. The role of ApoE itself in the neuritic degeneration is discussed [
133]. In
heterozygous V717F APP Tg mice, Aβ deposition was compared in mice expressing no ApoE, murine ApoE, or the various human ApoE isoforms (ApoE2, E3, and E4). As previously shown, ApoE was not necessary but it enhanced the formation of fibrillar Aβ. Murine ApoE was the most efficient, then human ApoE4, E3 and E2. In other words, as in man, ApoE2 and ApoE3 delayed the formation of amyloid deposits when compared to murine ApoE and human ApoE4 [
94]. In Tg mice bearing one allele of the Swedish mutation (APP
sw+/−), the expression of the human ApoE4 (ApoE4+/−) (under the human transferrin promoter) accelerated Aβ deposition and amyloid formation [
47]. However, in another study, the overexpression of human ApoE4 under a murine prion protein promoter (responsible for neuronal and glial expression) did not modify the amount and progression of Aβ deposition in Tg mice expressing human APP
swe or APP
swe and PS1 with the deletion of exon 9 [
193]. Van Dooren et al. compared the effects of expressing human ApoE4 in neurons (thy1 gene promoter) or in glia (GFAP gene promoter) in hAPP V717I singly transgenic and APP-V717I × PS1-A246E doubly transgenic mice (thy1 gene promoter for both transgenes). All of the mice were female and hemizygous for the transgene. The thy1 gene promoter construct is practically unexpressed in the thalamus. The presence of the human ApoE4 allele had a differential effect on cortex and thalamus, which also depended on its production cells (neuronal or glial): in the cortex, neuronal ApoE4 increased the number of diffuse deposits of Aβ, while in the thalamus, the density of both diffuse and focal deposits increased with neuronal and with glial ApoE. Neuronal ApoE promoted cortical amyloid angiopathy, while both neuronal and glial ApoE had a similar effect on the thalamus. ApoE did not influence APP processing and was not associated with tau hyperphosphorylation (probably because the ApoE transgene was hemizygous) [
314]. Since APP was not produced in the thalamus in these constructs, the accumulation of diffuse or focal Aβ in this topography was related to its migration.