The Absence of ABCA1 Decreases Soluble ApoE Levels but Does Not Diminish Amyloid Deposition in Two Murine Models of Alzheimer Disease

Abstract

ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate ␤-amyloid (A␤) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable A␤ levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/ PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/ PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo.Alzheimer disease (AD) 8 is the most common cause of senile dementia and currently affects ϳ40% of the population over 80 years of age. Clinically, AD is characterized by severe impairments in memory and executive cortical functions as well as difficulties in language, calculation, visuospatial perception, behavior, and judgment (1). Characteristic neuropathological hallmarks of AD include intraneuronal fibrillary tangles composed of hyperphosphorylated tau protein and amyloid deposits that are composed largely of A␤ peptides, apolipoprotein E (apoE), lipids, and other proteins that accumulate in the neural parenchyma and the cerebrovasculature (2, 3). A␤ peptides are a heterogeneous group of peptides 39 -43 amino acids in length that are proteolytically cleaved from amyloid precursor protein (APP) by ␥-and ␤-secretases (4, 5). A␤40 and A␤42 are the main A␤ species in the brain. A␤42 is less soluble and is present in all types of senile plaques, whereas A␤40 is the major species deposited in cerebral blood vessels (4 -7).Most affected individuals have late onset AD that typically manifests after 70 years of age. However, a number of families develop the disease in their 4th or 5th decades (8, 9). The cases of familial AD result from mutations within APP or secretase components (8, 10). For example, the Swedish mutation (K670M/N671L) increases the amount of A␤ peptide that is generated from APP (11, 12). Other APP mutations, including the Dutch (E693D) and Iowa (Q694N) mutations, alter the charge of the A␤ peptide and result in amyloid deposition predominantly in the cerebral blood vessels rather than in the parenchyma (13-16). In addition to mutations in APP, over 100 different mutations have been identified in presenilin-1 alone (17). However, less than 5% of the overall clinical burden of AD is caused by mutations in APP and presenilins combined.To date, the only well established risk factor for late-onset AD is apoE (18,19). In the hum...

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

“…In ABCA1-deficient APP/PS1 mice, low dose GW3965 tended to increase A␤40 and A␤42 levels in both carbonate-and guanidine-soluble pools in both cortex and hippocampus, particularly in animals in the therapeutic arm, although no increase reached statistical significance. These observations are consistent with previous studies showing that that loss of ABCA1 does not markedly affect baseline A␤ levels (7,8,11,14) and that less than 30 mg/kg/day of the LXR agonist TO901317 for 7 days does not alter A␤ levels in Tg2576 mice (29). APP/PS1 mice treated with high dose (33 mg/kg/day) GW3965 for 8 weeks showed elevated carbonate-soluble A␤40 and A␤42 in both cortex and hippocampus.…”

“…In peripheral tissues, the primary apolipoprotein acceptor for ABCA1 activity is apoA-I (18 -20), whereas it is apoE in the brain (6,9). Deficiency of murine ABCA1 leads to poorly lipidated apoE in the central nervous system (6,9), which facilitates the formation of amyloid deposits in AD mice (7,8,11). Conversely, selective overexpression of ABCA1 by 6-fold or more is sufficient to increase central nervous system apoE lipidation and prevent the formation of amyloid plaques in mice (10).…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…ATP-binding cassette A1 (ABCA1) normally lipidates apoE in the brain. When APP Tg mice are crossed onto an Abca1 2/2 background, this decreases apoE lipidation and increases amyloid deposition (Hirsch-Reinshagen et al 2005;Koldamova et al 2005a;Wahrle et al 2005), whereas increasing ABCA1 increases apoE lipidation and decreases amyloid deposition (Wahrle et al 2008).…”

ABC transporters, neural stem cells and neurogenesis – a different perspective

“…With its expression in liver and brain, ABCB1 -the prototype of the B subclass of transporters -and ABCA1 regulate the high-density lipoprotein levels in the plasma and cholesterol contents of several cell types in these organs [106][107][108][109][110][111][112][113][114]. Most interestingly, the ABCB1 transporter also shows strong expression in neurons of the hippocampus formation, particularly in the granule cells of the DG [85].…”