Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin

Grimm, Marcus O. W.; Grimm, Heike S.; Pätzold, Andreas J; Zinser, Eva G.; Halonen, Riikka; Duering, Marco; Tschäpe, Jakob Andreas; Strooper, Bart De; Müller, Ulrike; Shen, Jie; Hartmann, Tobias

doi:10.1038/ncb1313

Cited by 397 publications

(349 citation statements)

References 30 publications

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“…SPHs are precursors for ceramide production. Their accumulation induces apoptosis and seems to worsen neurodegeneration by increasing Aβ biosynthesis and promoting gamma-secretase processing of APP (Cutler et al, 2004;Grimm et al, 2005;Puglielli et al, 2003). Our findings closely resemble other work showing that global brain levels of ceremides, sphingolipids and related molecules are increased in the cerebral cortex of APP SL /PS1Ki and APP/PS1 mice especially after the age of 6 months (Barrier et al, 2010).…”

Section: Discussionsupporting

confidence: 89%

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

Pan

Nasaruddin

Elliott

et al. 2016

Neurobiology of Aging

102

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The pathogenesis of Alzheimer's disease (AD) is complex involving multiple contributing factors. The extent to which AD pathology impacts upon the metabolome is still not understood, nor is it known how disturbances change as the disease progresses. For the first time we have profiled longitudinally (6, 8, 10, 12 and 18 months) both the brain and plasma metabolome of APP/PS1 double transgenic and wild type (WT) mice. A total of 187 metabolites were quantified using a targeted metabolomics methodology. Multivariate statistical analysis produced models that distinguished APP/PS1 from WT mice at 8, 10 and 12 months. Metabolic pathway analysis found perturbed polyamine metabolism in both brain and blood plasma. There were other disturbances in essential amino acids, branched chain amino acids and also in the neurotransmitter serotonin. Pronounced imbalances in phospholipid and acylcarnitine homeostasis was evident in two age groups. AD-like pathology therefore impacts greatly on both the brain and blood metabolomes, although there appears to be a clear temporal sequence whereby changes to brain metabolites precede those in blood.

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Section: Discussionsupporting

confidence: 89%

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

Pan

Nasaruddin

Elliott

et al. 2016

Neurobiology of Aging

102

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“…ABCA1 was up-regulated at lower doses than apoE, consistent with previous observations that apoE is less sensitive to LXR-mediated induction (13,14,29). Unlike previous reports in Tg2576 mice, we did not observe selective responses of ABCA1 in the hippocampus, perhaps reflecting differences among animal models, particularly if PS1 mutations are included as these have been implicated in bi-directional regulatory loops involving cholesterol and sphingomyelin homeostasis and APP processing (41). Low dose GW3965 did not affect total APP levels or processing in APP/PS1 mice, but high dose GW3965 led to a trend toward increased production of CTF␣ and CTF␤ in hippocampus.…”

Section: Discussionsupporting

confidence: 47%

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*

Donkin

Stukas

Hirsch‐Reinshagen

et al. 2010

Journal of Biological Chemistry

169

142

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The cholesterol transpoter ATP-binding cassette transporter A1 (ABCA1) moves lipids onto apolipoproteins including apolipoprotein E (apoE), which is the major cholesterol carrier in the brain and an established genetic risk factor for late-onset Alzheimer disease (AD). In amyloid mouse models of AD, ABCA1 deficiency exacerbates amyloidogenesis, whereas ABCA1 overexpression ameliorates amyloid load, suggesting a role for ABCA1 in A␤ metabolism. Agonists of liver X receptors (LXR), including GW3965, induce transcription of several genes including ABCA1 and apoE, and reduce A␤ levels and improve cognition in AD mice. However, the specific role of ABCA1 in mediating beneficial responses to LXR agonists in AD mice is unknown. We evaluated behavioral and neuropathogical outcomes in GW3965-treated female APP/PS1 mice with and without ABCA1. Treatment of APP/PS1 mice with GW3965 increased ABCA1 and apoE protein levels. ABCA1 was required to observe significantly elevated apoE levels in brain tissue and cerebrospinal fluid upon therapeutic (33 mg/kg/day) GW3965 treatment. At 33 mg/kg/day, GW3965 was also associated with a trend toward redistribution of A␤ to the carbonate-soluble pool independent of ABCA1. APP/PS1 mice treated with either 2.5 or 33 mg/kg/day of GW3965 showed a clear trend toward reduced amyloid burden in hippocampus and whole brain, whereas APP/ PS1-treated mice lacking ABCA1 failed to display reduced amyloid load in the whole brain and showed trends toward increased hippocampal amyloid. Treatment of APP/PS1 mice with either dose of GW3965 completely restored novel object recognition memory to wild-type levels, which required ABCA1. These results suggest that ABCA1 contributes to several beneficial effects of the LXR agonist GW3965 in APP/PS1 mice.Lipid metabolism is increasingly recognized to play a key role in the pathogenesis of Alzheimer disease (AD), 4 which is the leading cause of dementia in the elderly (1). AD is characterized by the presence of two neuropathological hallmarks including extracellular amyloid plaques that consist mainly of aggregated A␤ peptides and intracellular neurofibrillary tangles consisting of hyperphosphorylated Tau protein (2). Although the pathogenesis of AD is not completely understood, a leading hypothesis is that aberrant metabolism of A␤ peptides, which are derived by proteolytic cleavage from amyloid precursor protein (APP), triggers many of the toxic events in AD and eventually leads to both Tau and amyloid pathologies (3). Less than 5% of AD patients exhibit disease onset in their 40s and 50s due to genetic mutations that lead to increased production of A␤ peptides, particularly of the most detrimental A␤42 species (4). The cause of AD in more than 95% of subjects that typically develop AD in late life is unknown. As production of A␤ is generally not altered in these patients, age-related defects in A␤ degradation and clearance is emerging as a leading hypothesis for development of AD in the majority of patients (5).In mice, apoE exists in only one allelic state, ...

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“…5). Modulation of APP processing by various membrane lipids has been extensively described (47): brain lipids are required to reconstitute fully the activity of the ␥-secretase (38), and several single lipid components directly modulate ␥-secretase activity (47). Thus, it is plausible that changes in PIP 2 levels give rise to a change in the composition of the lipid environment where the ␥-secretase complex resides, thereby altering its proteolytic activity.…”

Section: Discussionmentioning

confidence: 99%

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

Landman

Jeong

Shin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

125

116

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Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP 2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP 2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg 2؉ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP 2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP 2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP 2 closely correlates with 42-residue amyloid ␤-peptide (A␤42) levels. Our data suggest that PIP 2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic A␤42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP 2 may offer a therapeutic approach in Alzheimer's disease.␤-amyloid precursor protein ͉ channel ͉ secretase ͉ transient receptor potential melastatin 7 (TRPM7) ͉ capacitative calcium entry

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Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin

Cited by 397 publications

References 30 publications

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

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*

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

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