Greasing the wheels of Aβ clearance in Alzheimer's Disease: The role of lipids and apolipoprotein E

Abstract

Although apolipoprotein E (apoE) is the most common genetic risk factor for Alzheimer's Disease (AD), how apoE participates in AD pathogenesis remains incompletely understood. ApoE is also the major carrier of lipids in the brain. Here, we review studies showing that the lipidation status of apoE influences the metabolism of Abeta peptides, which accumulate as amyloid deposits in the neural parenchyma and cerebrovasculature. One effect of apoE is to inhibit the transport of Abeta across the blood-brain-barrier (BBB), particularly when apoE is lipidated. A second effect is to facilitate the proteolytic degradation of Abeta by neprilysin and insulin degrading enzyme (IDE), which is enhanced when apoE is lipidated. We also describe how apoE becomes lipidated and how this impacts Abeta metabolism. Specifically, genetic loss of the cholesterol transporter ABCA1 impairs apoE lipidation and promotes amyloid deposition in AD mouse models. ABCA1 catalyses the ATP-dependent transport of cholesterol and phospholipids from the plasma membrane to lipid-free apolipoproteins including apoE. Conversely, selective overexpression of ABCA1 increases apoE lipidation in the central nervous system (CNS) and eliminates the formation of amyloid plaques in vivo. Deficiency of Liver-X-Receptors (LXRs), transcription factors that stimulate ABCA1 and apoE expression, exacerbates AD pathogenesis in vivo, whereas treatment of AD mice with synthetic LXR agonists reduces amyloid load and improves cognitive performance. These studies provide new insights into the mechanisms by which apoE affects Abeta metabolism, and offer opportunities to develop novel therapeutic approaches to reduce the leading cause of dementia in the elderly.

Rosiglitazone Rescues Memory Impairment in Alzheimer's Transgenic Mice: Mechanisms Involving a Reduced Amyloid and Tau Pathology

“…In keeping with these data, increased expression of Abca1, without modifications in ApoE levels, appears to be sufficient for the reduction in Ab levels in PDAPP transgenic mice (Wahrle et al, 2008). On the other hand, deficiency of LXRs, transcription factors that promote Abca1 and ApoE expression, exacerbates AD pathology in vivo, whereas treatment of Alzheimer's mice with synthetic LXR agonists reduces amyloid load and improves cognitive performance (Fan et al, 2009). Here, we failed to observe changes in LXRs expression after rosiglitazone treatment.…”

Retinoic Acid Isomers Facilitate Apolipoprotein E Production and Lipidation in Astrocytes through the Retinoid X Receptor/Retinoic Acid Receptor Pathway

“…In fact, deletion of ABCA1 in APP transgenic mice exacerbates A␤ deposition by suppressing apoE lipidation and accelerating its turnover (56 -58). ABCA1 overexpression increases lipidated apoE levels and reduces the formation of amyloid plaques in amyloid model mice (59,60). LXR agonists or RXR agonists also reduce A␤ deposition by increasing apoE and ABCA1 levels in amyloid model mice (18 -21).…”

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

“…At the blood-brain barrier (BBB), LRP-1 is involved in Ab clearance from brain and the decrease in BBB LRP-1 levels that occurs in AD has been postulated as one reason why Ab builds up in the brain (Figure 1(b)). [8][9][10] This protein is primarily produced by astrocytes 11 and is responsible for neuronal maintenance and repair. APOE is also important in repairing the BBB after injury, [12][13][14] and dysfunction of the BBB has been considered to be both a cause and a consequence of AD.…”

“…17 Perivascular removal of Ab is hindered with the expression of E4, which was shown in many in vitro studies as well as in mice expressing human E4. 10,18 This decreased drainage, in turn, leads to decreased clearance of Ab peptides and increased amyloid plaques, as well as other pathophysiologic features such as alterations in the neurovascular unit and BBB function. 12,14,[19][20][21][22] APOE is involved in preserving the integrity of the BBB.…”