, 2009; Mahley et al., 2006). ApoE clearly interacts with the Aβ pathway; however, there is abundant evidence showing that apoE (apoE4 > apoE3 > apoE2) also can directly impact the pathogenesis of AD and other neurodegenerative

Autophagy Compound high throughput screening disorders independent of Aβ. As clinical trials targeting the lowering of amyloid and the Aβ peptide fail to impact AD cognitive decline and neurodegeneration (Selkoe, 2011), alternative mechanisms must be considered, and the critical importance of apoE in pathogenesis further acknowledged. Under normal physiological conditions, apoE is synthesized primarily by astrocytes in the brain to support lipid transport and membrane repair processes (Mahley, 1988). In contrast, apoE synthesis in neurons usually occurs in response to neuronal insult or injury. Each of these processes is designed to protect neuronal integrity and promote neuronal repair, respectively, but in fact can be directly injurious when apoE4 is expressed in neurons. Indeed, apoE4 expression is associated with poor clinical outcome or accelerated/more severe progression in numerous neurological disorders. This finding strongly suggests that while apoE participates in general cellular pathway(s) designed to respond adaptively to various environmental,

metabolic, or genetic stimuli, its expression can also increase the likelihood of neurodegeneration. Several pathways for this have been suggested. ApoE is known to exhibit isoform-specific effects on blood-brain barrier (BBB) integrity in mouse models (Bell et al., 2012). GW-572016 supplier In either target replacement mice or glial fibrillary acidic protein promoter transgenic mice, apoE4 expression increases the BBB’s susceptibility to injury by activating the proinflammatory cytokine else cyclophilin A in pericytes and triggering the NF-κB/matrix metalloproteinase 9 pathway. Interestingly, BBB breakdown is independent of Aβ. The subsequent

neuronal damage that occurs appears to result from the leakage of blood-derived proteins—including immunoglobulin G, thrombin, and fibrin—into the brain. The extravasation of blood proteins has been implicated in the activation of numerous neurotoxic pathways. For example, in a mouse model of multiple sclerosis, fibrinogen leakage and fibrin deposition in the brain activate microglia and lead to neuropathology (Adams et al., 2007; Akassoglou et al., 2004; Davalos and Akassoglou, 2012). As will be discussed, BBB leakage could represent an additional insult linked to neuronal injury and the induction of neuronal apoE synthesis and neurotoxicity. ApoE is also involved in maintaining and regulating synaptic activity and strength in knockin mice and hippocampal slices. Specifically, apoE4 reduces neuronal cell-surface expression of the apoE receptor 2, as well as N-methyl-d-aspartate and AMPA receptors, by sequestering them in an intracellular compartment ( Chen et al., 2010).