Intraneuronal amyloid‐β plays a role in mediating the synergistic pathological effects of apoE4 and environmental stimulation

Abstract

The allele E4 of apolipoprotein E4 (apoE4), which is the most prevalent genetic risk factor of Alzheimer's disease (AD), inhibits synaptogenesis and neurogenesis and stimulates apoptosis in brains of apoE4 transgenic mice that have been exposed to an enriched environment. In the present study, we investigated the hypothesis that the brain activity-dependent impairments in neuronal plasticity, induced by apoE4, are mediated via the amyloid cascade. Importantly, we found that exposure of mice transgenic for either apoE4, or the Alzheimer's disease benign allele apoE3, to an enriched environment elevates similarly the hippocampal levels of amyloid-b peptide (Ab) and apoE of these mice, but that the degree of aggregation and spatial distribution of Ab in these mice are markedly affected by the apoE genotype. Accordingly, environmental stimulation triggered the formation of extracellular plaque-like Ab deposits and the accumulation of intra-neuronal oligomerized Ab specifically in brains of apoE4 mice. Further experiments revealed that hippocampal dentate gyrus neurons are particularly susceptible to apoE4 and environmental stimulation and that these neurons are specifically enriched in both oligomerized Ab and apoE. These findings show that the impairments in neuroplasticity which are induced by apoE4 following environmental stimulation are associated with the accumulation of intraneuronal Ab and suggest that oligomerized Ab mediates the synergistic pathological effects of apoE4 and environmental stimulation.

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

“…We found no evidence for endogenous mouse Aβ aggregation in the human Aβ injection model (Figs. 4a, b and 7a), consistent with previous findings [36,37].…”

New Insights into the Roles of Endolysosomal Cathepsins in the Pathogenesis of Alzheimers Disease: Cathepsin Inhibitors as Potential Therapeutics

“…Thus, cysteinyl proteases could represent new drug targets for the attenuation of AD. Increased Cat B activity has been previously implicated in the degeneration of axon and myelin in demyelinating diseases as well as in spinal cord injury and brain trauma [52][53][54][55][56].…”

“…Thus, proper functioning of the endolysosomal proteases is critical for normal cellular activity and viability. Proteolysis of APP as well as apolipoprotein E (apoE) has been implicated in the pathogenesis of AD [52][53][54][55]. Studies using human brain homogenates have shown that cathepsins play a crucial role in the proteolysis of APP and apoE.…”

Critical role of intraneuronal Aβ in Alzheimer's disease: Technical challenges in studying intracellular Aβ

“…Remarkably, early intraneuronal Aβ accumulation was first seen to occur in AD-vulnerable neurons in human brains with Down syndrome even before plaque deposition (Gouras et al, 2000; Gyure et al, 2001; Busciglio et al, 2002; Mori et al, 2002; Cataldo et al, 2004). Intraneuronal Aβ was also detected in postmortem brain tissue in mild cognitive impairment and AD (Gouras et al, 2000; D'Andrea et al, 2001; Ohyagi et al, 2005), as well as in AD transgenic models (Wirths et al, 2001; Takahashi et al, 2002; Oddo et al, 2003; Sheng et al, 2003; Echeverria et al, 2004; Lord et al, 2006; Knobloch et al, 2007; Levi et al, 2007; Espana et al, 2010; Gandy et al, 2010). This Aβ accumulation in AD vulnerable neurons preceded the presence of hyperphosphorylated tau.…”