Neuronal or Glial Expression of Human Apolipoprotein E4 Affects Parenchymal and Vascular Amyloid Pathology Differentially in Different Brain Regions of Double- and Triple-Transgenic Mice

Abstract

Apolipoprotein E4 (ApoE4) is associated with Alzheimer's disease by unknown mechanisms. We generated six transgenic mice strains expressing human ApoE4 in combination with mutant amyloid precursor protein (APP) and mutant presenilin-1 (PS1) in single-, double-, or triple-transgenic combinations. Diffuse, but not dense, amyloid plaque-load in subiculum and cortex was increased by neuronal but not glial ApoE4 in old (15 months) double-transgenic mice, whereas both diffuse and dense plaques formed in thalamus in both genotypes. Neuronal and glial ApoE4 promoted cerebral amyloid angiopathy as extensively as mutant PS1 but with pronounced regional differences: cortical angiopathy was induced by neuronal ApoE4 while thalamic angiopathy was again independent of ApoE4 source. Angiopathy correlated more strongly with soluble A␤40 and A␤42 levels in cortex than in thalamus throughout the six genotypes. Neither neuronal nor glial ApoE4 affected APP proteolytic processing, as opposed to mutant PS1. Neuronal ApoE4 increased soluble amyloid levels more than glial ApoE4, but the A␤42/40 ratios were similar, although significantly higher than in single APP transgenic mice. We conclude that although the cellular origin of ApoE4 differentially affects regional amyloid pathology, ApoE4 acts on the disposition of amyloid peptides downstream from their excision from APP but without induction of tauopathy. Alzheimer's disease (AD) is characterized by pathological accumulations in the brain of extracellular amyloid plaques and intraneuronal accumulations of protein tau known as neurofibrillary tangles. The amyloid peptides A␤40 and A␤42 are the major components of the amyloid deposits in parenchyma and vasculature.1 The amyloid peptides are excised from the integral membrane protein amyloid precursor protein (APP) by sequential endoproteolytic cleavages by ␤-and ␥-secretases.2 The exact causes and consequences, in terms of normal processes and mechanisms that are disturbed by the amyloid peptides and causing neurodegeneration, remain primarily unclear. 3Besides APP and presenilins (PS1, PS2), the apolipoprotein E (ApoE) is genetically linked to AD. 4 The ApoE4 lipoprotein or its encoding ⑀4 allele, are epidemiologically associated with AD and confer an increased risk and earlier age of onset relative to the more common ApoE3 protein or ⑀3 allele. [5][6][7] ApoE is a 34-kd protein abundantly expressed in liver and brain. In the circulation, ApoE-lipoproteins mediate transport of lipids and cholesterol from and to liver and extrahepatic tissues. In contrast to the peripheral functions of ApoE that are well understood, details of its actions in the central nervous system remain primarily unknown. Actually, the epidemiological association of the ⑀4-allele to AD provided a strong impetus to research, by pointing out our lack of understanding the physiology of lipid and cholesterol homeostasis and of their transport in brain, in particular the contribution of ApoE and various ApoE receptors. 8,9

Tg-SwDI Transgenic Mice Exhibit Novel Alterations in AβPP Processing, Aβ Degradation, and Resilient Amyloid Angiopathy

“…In A␤PP and PS1 Tg mice, the thalamic deposition of vascular amyloid is mediated by glial Apo E expression. 34 Our observations indicate that in the Tg-SwDI mice there is an intimate association between vascular amyloid deposits and Apo E. Furthermore, the lack of endogenous mouse Apo E, as in the Tg-SwDI with Apo E knockout mice, severely reduces thalamic microvascular amyloid deposition. 35 Interestingly, the C57BL/6 mouse, the background strain used in this study, appears to be more susceptible to age-dependent atherosclerosis and arteriosclerosis than other mice.…”

Aβ40 Inhibits Amyloid DepositionIn Vivo

“…This is a surprising result given that A␤40 is reported to be the predominant A␤ species deposited in vessels (Gravina et al, 1995). Although previous studies suggested that a higher ratio of A␤40 to A␤42 might promote the formation of CAA over parenchymal deposition (Herzig et al, 2004;, in other studies, selective increases in A␤42 were associated with more CAA (Van Dorpe et al, 2000;Samura et al, 2006;Van Dooren et al, 2006). Our previous studies showed that high-level production of wild-type A␤40 by itself is not sufficient to cause CAA .…”

Rodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice

“…Experimental manipulations such as co-expressing human apoE4 with APPswe (48), or introducing the E693Q Dutch mutation into APP transgenic mice (49), both elevated the ratio of A␤40:42 and caused redistribution of amyloid deposits from the parenchyma to the vasculature. Conversely, several experiments designed to specifically lower the production of A␤40 relative to A␤42, such as co-expressing mutant PS1 with APP (50,51) or expressing an A␤42-exclusive transgene (52), are also reported to increase cerebral amyloid angiopathy in transgenic mice. Our current results are most consistent with the hypothesis that lowering A␤40:42 increases the appearance of vascular amyloid.…”