Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer's disease.

In Alzheimer's disease (AD), disturbed homeostasis of the proteases competing for amyloid precursor protein processing has been reported: a disintegrin and metalloproteinase 10 (ADAM10), the physiological α-secretase, is decreased in favor of the amyloid-ß-generating enzyme BACE-1. To identify transcription factors that modulate the expression of either protease, we performed a screening approach: 48 transcription factors significantly interfered with ADAM10/BACE-1-promoter activity. One selective inducer of ADAM10 gene expression is the X-box binding protein-1 (XBP-1). This protein regulates the unfolded protein-response pathway. We demonstrate that particularly the spliced XBP-1 variant dose dependently regulates ADAM10 expression, which can be synergistically enhanced by 100 nM insulin. Analysis of 2 different transgenic mouse models (APP/PS1 and 5xFAD) revealed that at early time points in pathology XBP-1 metabolism is induced. This is accompanied by a 2-fold augmented ADAM10 amount as compared with nontransgenic littermates (P=0.011). Along with aging of the mice, the system is counterregulated, and XBP-1 together with ADAM10 expression level decreased to ∼50% as compared with control animals. Analyses of expression levels in human AD brains showed that ADAM10 mRNA correlated with active XBP-1 (r=0.3120), but expression did not reach levels of healthy age-matched controls, suggesting deregulation of XBP-1 signaling. Our results demonstrate that XBP-1 is a driver of ADAM10 gene expression and that disturbance of this pathway might contribute to development or progression of AD.

Plant sterols the better cholesterol in Alzheimer's disease? A mechanistical study.

Amyloid-ß (Aß), major constituent of senile plaques in Alzheimer's disease (AD), is generated by proteolytic processing of the amyloid precursor protein (APP) by ß- and γ-secretase. Several lipids, especially cholesterol, are associated with AD. Phytosterols are naturally occurring cholesterol plant equivalents, recently been shown to cross the blood-brain-barrier accumulating in brain. Here, we investigated the effect of the most nutritional prevalent phytosterols and cholesterol on APP processing. In general, phytosterols are less amyloidogenic than cholesterol. However, only one phytosterol, stigmasterol, reduced Aß generation by (1) directly decreasing ß-secretase activity, (2) reducing expression of all γ-secretase components, (3) reducing cholesterol and presenilin distribution in lipid rafts implicated in amyloidogenic APP cleavage, and by (4) decreasing BACE1 internalization to endosomal compartments, involved in APP ß-secretase cleavage. Mice fed with stigmasterol-enriched diets confirmed protective effects in vivo, suggesting that dietary intake of phytosterol blends mainly containing stigmasterol might be beneficial in preventing AD.

PS dependent APP cleavage regulates glucosylceramide synthase and is affected in Alzheimer's disease.

BACKGROUND: Gangliosides were found to be associated with Alzheimer's disease (AD). Here we addressed a potential function of γ-secretase (presenilin) dependent cleavage of the amyloid-precursor-protein (APP) in the regulation of ganglioside de novo synthesis. METHODS: To identify a potential role of γ-secretase and APP in ganglioside de novo synthesis we used presenilin (PS) deficient and APP deficient cells and mouse brains, mutated PS as well as transgenic mice and AD post mortem brains. Changes in glucosylceramide synthase (GCS) activity were identified by incorporation of radiolabeled UDP-glucose in glucosylceramide, changes in gene expression via real-time PCR and Western blot analysis. Alterations in ganglioside levels were determined by thin layer chromatography and mass spectrometry. RESULTS: We found that PS and APP deficiency, in vitro and in vivo, resulted in increased GCS gene expression, elevated enzyme activity and thus increased glucosylceramide and total ganglioside level. Using a specific γ-secretase inhibitor revealed that PS proteolytic activity alters ganglioside homeostasis. By the use of mutated PS causing early onset AD in cell culture and transgenic mice we found that GCS is increased in AD, further substantiated by the use of AD post mortem brains, suffering from sporadic AD. CONCLUSION: APP processing regulates ganglioside de novo synthesis and is affected in AD.

Impact of Vitamin D on amyloid precursor protein processing and amyloid-ß peptide degradation in Alzheimer's disease.

Ninety percent of the elderly population has a vitamin D hypovitaminosis, and several lines of evidence suggest that there might be a potential causal link between Alzheimer's disease (AD) and a non-sufficient supply with vitamin D. However, the mechanisms linking AD to vitamin D have not been completely understood. The aim of our study is to elucidate the impact of 25(OH) vitamin D3 on amyloid precursor protein processing in mice and N2A cells utilizing very moderate and physiological vitamin D hypovitaminosis in the range of 20-30% compared to wild-type mice. We found that already under such mild conditions, amyloid-ß peptide (Aß) is significantly increased, which is caused by an increased ß-secretase activity and BACE1 protein level. Additionally, neprilysin (NEP) expression is downregulated resulting in a decreased NEP activity further enhancing the effect of decreased vitamin D on the Aß level. In line with the in vivo findings, corresponding effects were found with N2A cells supplemented with 25(OH) vitamin D3. Our results further strengthen the link between AD and vitamin D3 and suggest that supplementation of vitamin D3 might have a beneficial effect in AD prevention.

A bidirectional link between sulfatide and Alzheimer's disease.

Reduced sulfatide level is found in Alzheimer's disease (AD) patients. Here, we demonstrate that amyloid precursor protein (APP) processing regulates sulfatide synthesis and vice versa. Different cell culture models and transgenic mice models devoid of APP processing or in particular the APP intracellular domain (AICD) reveal that AICD decreases Gal3st1/CST expression and subsequently sulfatide synthesis. In return, sulfatide supplementation decreases Aß generation by reducing ß-secretase (BACE1) and γ-secretase processing of APP. Increased BACE1 lysosomal degradation leads to reduced BACE1 protein level in endosomes. Reduced γ-secretase activity is caused by a direct effect on γ-secretase activity and reduced amounts of γ-secretase components in lipid rafts. Similar changes were observed by analyzing cells and mice brain samples deficient of arylsulfatase A responsible for sulfatide degradation or knocked down in Gal3st1/CST. In line with these findings, addition of sulfatides to brain homogenates of AD patients resulted in reduced γ-secretase activity. Human brain APP level shows a significant negative correlation with GAL3ST1/CST expression underlining the in vivo relevance of sulfatide homeostasis in AD.

Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by extracellular accumulation of amyloid-ß peptide (Aß), generated by proteolytic processing of the amyloid precursor protein (APP) by ß- and γ-secretase. Aß generation is inhibited when the initial ectodomain shedding is caused by α-secretase, cleaving APP within the Aß domain. Therefore, an increase in α-secretase activity is an attractive therapeutic target for AD treatment. APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to influence APP processing. Although several studies have focused on γ-secretase, the effect of the membrane lipid microenvironment on α-secretase is poorly understood. In the present study, we systematically investigated the effect of fatty acid (FA) acyl chain length (10:0, 12:0, 14:0, 16:0, 18:0, 20:0, 22:0, 24:0), membrane polar lipid headgroup (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine), saturation grade and the FA double-bond position on α-secretase activity. We found that α-secretase activity is significantly elevated in the presence of FAs with short chain length and in the presence of polyunsaturated FAs, whereas variations in the phospholipid headgroups, as well as the double-bond position, have little or no effect on α-secretase activity. Overall, our study shows that local lipid membrane composition can influence α-secretase activity and might have beneficial effects for AD.

Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms.

Alzheimer disease is characterized by accumulation of the ß-amyloid peptide (Aß) generated by ß- and γ-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing ß- and γ-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of α-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in γ-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aß release. DHA has a typical pleiotropic effect; DHA-mediated Aß reduction is not the consequence of a single major mechanism but is the result of combined multiple effects.

Plasmalogens inhibit APP processing by directly affecting γ-secretase activity in Alzheimer's disease.

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD). Previously it has been shown that plasmalogens, the major brain phospholipids, are altered in AD. However, it remained unclear whether plasmalogens themselves are able to modulate amyloid precursor protein (APP) processing or if the reduced plasmalogen level is a consequence of AD. Here we identify the plasmalogens which are altered in human AD postmortem brains and investigate their impact on APP processing resulting in Aß production. All tested plasmalogen species showed a reduction in γ-secretase activity whereas ß- and α-secretase activity mainly remained unchanged. Plasmalogens directly affected γ-secretase activity, protein and RNA level of the secretases were unaffected, pointing towards a direct influence of plasmalogens on γ-secretase activity. Plasmalogens were also able to decrease γ-secretase activity in human postmortem AD brains emphasizing the impact of plasmalogens in AD. In summary our findings show that decreased plasmalogen levels are not only a consequence of AD but that plasmalogens also decrease APP processing by directly affecting γ-secretase activity, resulting in a vicious cycle: Aß reduces plasmalogen levels and reduced plasmalogen levels directly increase γ-secretase activity leading to an even stronger production of Aß peptides.

Role of amyloid beta in lipid homeostasis.

Alzheimer's disease (AD), the most common neurodegenerative disorder, which affects more than 35 million people worldwide, is characterized by a massive accumulation of tangles and amyloid plaques. Several risk factors linked to lipid homeostasis have been identified. Apolipoprotein E (ApoE), which also has a strong impact in coronary artery disease, is besides aging the most prominent risk factor in sporadic AD. High levels of lipoproteins and cholesterol increase the risk of AD and some cholesterol lowering drugs like statins seem to correlate with a reduced risk for dementia. Moreover, cholesterol increases amyloid beta (Abeta) production, which is derived from amyloid precursor protein (APP) by proteolytic processing. Beside cholesterol, other lipids that strongly modulate APP processing could be identified and interestingly the APP cleavage products itself regulate lipid homeostasis resulting in complex regulatory feedback cycles. Here, we review the mechanistic link of cholesterol and sphingolipid homeostasis and APP processing and the consequence of this bidirectional link for and in AD. Although cholesterol is the best studied brain lipid in AD, many other lipids are involved in the Abeta-lipid regulatory system and some of these lipids exceed the cholesterol effect on Abeta production [1-5]. This involvement is bidirectional. On the one hand, lipids control APP processing and, on the other hand, APP processing controls the levels of several key lipids [6, 7]. Beside the physiological function of APP processing in lipid homeostasis, under pathological conditions like AD, these regulating (feedback-) cycles are dysfunctional. Additionally, mutual influence of lipids and APP processing raises the question if altered lipid homeostasis is the cause or consequence of AD.

Plasmalogen synthesis is regulated via alkyl-dihydroxyacetonephosphate-synthase by amyloid precursor protein processing and is affected in Alzheimer's disease.

Lipids play an important role as risk or protective factors in Alzheimer's disease, which is characterized by amyloid plaques composed of aggregated amyloid-beta. Plasmalogens are major brain lipids and controversially discussed to be altered in Alzheimer's disease (AD) and whether changes in plasmalogens are cause or consequence of AD pathology. Here, we reveal a new physiological function of the amyloid precursor protein (APP) in plasmalogen metabolism. The APP intracellular domain was found in vivo and in vitro to increase the expression of the alkyl-dihydroxyacetonephosphate-synthase (AGPS), a rate limiting enzyme in plasmalogen synthesis. Alterations in APP dependent changes of AGPS expression result in reduced protein and plasmalogen levels. Under the pathological situation of AD, increased amyloid-beta level lead to increased reactive oxidative species production, reduced AGPS protein and plasmalogen level. Accordingly, phosphatidylethanol plasmalogen was decreased in the frontal cortex of AD compared to age matched controls. Our findings elucidate that plasmalogens are decreased as a consequence of AD and regulated by APP processing under physiological conditions.

Profiling of Alzheimer's disease related genes in mild to moderate vitamin D hypovitaminosis.

A vast majority of the elderly population shows a mild to moderate vitamin D deficiency. Besides the well-known function of vitamin D, vitamin D receptor is also expressed in brain and is discussed to regulate several genes. However very little is known whether genes are regulated, associated with Alzheimer's disease (AD). Here we investigate 117 genes, known to be affected in AD, in mouse brain samples with a mild vitamin D hypovitaminosis comparable to the vitamin D status of the elderly population (20%-30% deficiency). The 117 genes include two positive controls, Nep and Park7, already known to be affected by both AD and vitamin D hypovitaminosis. The 25 most promising candidates were verified in a second independent mouse cohort, resulting in eleven genes further evaluated against three additional housekeeping genes. Three of the remaining eight significantly altered genes are involved in APP homeostasis (Snca, Nep, Psmb5), and each one gene in oxidative stress (Park7), inflammation (Casp4), lipid metabolism (Abca1), signal transduction (Gnb5) and neurogenesis (Plat). Our results tighten the link of vitamin D and AD and underline that vitamin D influences several genes also in brain, highlighting that a strong link not only to AD but also to other neurodegenerative diseases might exist.

Selective enhancement of the activity of C-terminally truncated, but not intact, acetylcholinesterase.

Acetylcholinesterase (AChE) is one of the fastest enzymes approaching the catalytic limit of enzyme activity. The enzyme is involved in the terminal breakdown of the neurotransmitter acetylcholine, but non-enzymatic roles have also been described for the entire AChE molecule and its isolated C-terminal sequences. These non-cholinergic functions have been attributed to both the developmental and degenerative situation: the major form of AChE present in these conditions is monomeric. Moreover, AChE has been shown to lose its typical characteristic of substrate inhibition in both development and degeneration. This study characterizes a form of AChE truncated after amino acid 548 (T548-AChE), whose truncation site is homologue to that of a physiological form of T-AChE detected in fetal bovine serum that has lost its C-terminal moiety supposedly due to proteolytic cleavage. Peptide sequences covered by this C-terminal sequence have been shown to be crucially involved in both developmental and degenerative mechanisms in vitro. Numerous studies have addressed the structure-function relationship of the AChE C-terminus with T548-AChE representing one of the most frequently studied forms of truncated AChE. In this study, we provide new insight into the understanding of the functional characteristics that T548-AChE acquires in solution: T548-AChE is incubated with agents of varying net charge and molecular weight. Together with kinetic studies and an analysis of different molecular forms and aggregation states of T548-AChE, we show that the enzymatic activity of T548-AChE, an enzyme verging at its catalytic limit is, nonetheless, apparently enhanced by up to 800%. We demonstrate, first, how the activity of T548-AChE can be enhanced through agents that contain highly positive charged moieties. Moreover, the un-competitive mechanism of activity enhancement most likely involves the peripheral anionic site of AChE that is reflected in delayed substrate inhibition being observed for activity enhanced T548-AChE. The data provides evidence towards a mechanistic and functional link between the form of AChE unique to both development and degeneration and a C-terminal peptide of T-AChE acting under those conditions.

APP intracellular domain derived from amyloidogenic ß- and γ-secretase cleavage regulates neprilysin expression.

Alzheimer's disease (AD) is characterized by an accumulation of Amyloid-ß (Aß), released by sequential proteolytic processing of the amyloid precursor protein (APP) by ß - and γ-secretase. Aß peptides can aggregate, leading to toxic Aß oligomers and amyloid plaque formation. Aß accumulation is not only dependent on de novo synthesis but also on Aß degradation. Neprilysin (NEP) is one of the major enzymes involved in Aß degradation. Here we investigate the molecular mechanism of NEP regulation, which is up to now controversially discussed to be affected by APP processing itself. We found that NEP expression is highly dependent on the APP intracellular domain (AICD), released by APP processing. Mouse embryonic fibroblasts devoid of APP processing, either by the lack of the catalytically active subunit of the γ-secretase complex [presenilin (PS) 1/2] or by the lack of APP and the APP-like protein 2 (APLP2), showed a decreased NEP expression, activity and protein level. Similar results were obtained by utilizing cells lacking a functional AICD domain (APPΔCT15) or expressing mutations in the genes encoding for PS1. AICD supplementation or retransfection with an AICD encoding plasmid could rescue the down-regulation of NEP further strengthening the link between AICD and transcriptional NEP regulation, in which Fe65 acts as an important adaptor protein. Especially AICD generated by the amyloidogenic pathway seems to be more involved in the regulation of NEP expression. In line, analysis of NEP gene expression in vivo in six transgenic AD mouse models (APP and APLP2 single knock-outs, APP/APLP2 double knock-out, APP-swedish, APP-swedish/PS1Δexon9, and APPΔCT15) confirmed the results obtained in cell culture. In summary, in the present study we clearly demonstrate an AICD-dependent regulation of the Aß-degrading enzyme NEP in vitro and in vivo and elucidate the underlying mechanisms that might be beneficial to develop new therapeutic strategies for the treatment of AD.

Upregulation of PGC-1α expression by Alzheimer's disease-associated pathway: presenilin 1/amyloid precursor protein (APP)/intracellular domain of APP.

Cleavage of amyloid precursor protein (APP) by ß- and γ-secretase generates amyloid-ß (Aß) and APP intracellular domain (AICD) peptides. Presenilin (PS) 1 or 2 is the catalytic component of the γ-secretase complex. Mitochondrial dysfunction is an established phenomenon in Alzheimer's disease (AD), but the causes and role of PS1, APP, and APP's cleavage products in this process are largely unknown. We studied the effect of these AD-associated molecules on mitochondrial features. Using cells deficient in PSs expression, expressing human wild-type PS1, or PS1 familial AD (FAD) mutants, we found that PS1 affects mitochondrial energy metabolism (ATP levels and oxygen consumption) and expression of mitochondrial proteins. These effects were associated with enhanced expression of the mitochondrial master transcriptional coactivator PGC-1α and its target genes. Importantly, PS1-FAD mutations decreased PS1's ability to enhance PGC-1α mRNA levels. Analyzing the effect of APP and its γ-secretase-derived cleavage products Aß and AICD on PGC-1α expression showed that APP and AICD increase PGC-1α expression. Accordingly, PGC-1α mRNA levels in cells deficient in APP/APLP2 or expressing APP lacking its last 15 amino acids were lower than in control cells, and treatment with AICD, but not with Aß, enhanced PGC-1α mRNA levels in these and PSs-deficient cells. In addition, knockdown of the AICD-binding partner Fe65 reduced PGC-1α mRNA levels. Importantly, APP/AICD increases PGC-1α expression also in the mice brain. Our results therefore suggest that APP processing regulates mitochondrial function and that impairments in the newly discovered PS1/APP/AICD/PGC-1α pathway may lead to mitochondrial dysfunction and neurodegeneration.

Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP).

Hydrogenation of oils and diary products of ruminant animals leads to an increasing amount of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Here we systematically investigate whether the regulated intramembrane proteolysis of the amyloid precursor protein (APP) is affected by trans fatty acids compared to the cis conformation. Our experiments clearly show that trans fatty acids compared to cis fatty acids increase amyloidogenic and decrease nonamyloidogenic processing of APP, resulting in an increased production of amyloid beta (Aß) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer's disease (AD). Moreover, our results show that oligomerization and aggregation of Aß are increased by trans fatty acids. The mechanisms identified by this in vitro study suggest that the intake of trans fatty acids potentially increases the AD risk or causes an earlier onset of the disease.

Amyloid precursor protein (APP) mediated regulation of ganglioside homeostasis linking Alzheimer's disease pathology with ganglioside metabolism.

Gangliosides are important players for controlling neuronal function and are directly involved in AD pathology. They are among the most potent stimulators of Aß production, are enriched in amyloid plaques and bind amyloid beta (Aß). However, the molecular mechanisms linking gangliosides with AD are unknown. Here we identified the previously unknown function of the amyloid precursor protein (APP), specifically its cleavage products Aß and the APP intracellular domain (AICD), of regulating GD3-synthase (GD3S). Since GD3S is the key enzyme converting a- to b-series gangliosides, it therefore plays a major role in controlling the levels of major brain gangliosides. This regulation occurs by two separate and additive mechanisms. The first mechanism directly targets the enzymatic activity of GD3S: Upon binding of Aß to the ganglioside GM3, the immediate substrate of the GD3S, enzymatic turnover of GM3 by GD3S was strongly reduced. The second mechanism targets GD3S expression. APP cleavage results, in addition to Aß release, in the release of AICD, a known candidate for gene transcriptional regulation. AICD strongly down regulated GD3S transcription and knock-in of an AICD deletion mutant of APP in vivo, or knock-down of Fe65 in neuroblastoma cells, was sufficient to abrogate normal GD3S functionality. Equally, knock-out of the presenilin genes, presenilin 1 and presenilin 2, essential for Aß and AICD production, or of APP itself, increased GD3S activity and expression and consequently resulted in a major shift of a- to b-series gangliosides. In addition to GD3S regulation by APP processing, gangliosides in turn altered APP cleavage. GM3 decreased, whereas the ganglioside GD3, the GD3S product, increased Aß production, resulting in a regulatory feedback cycle, directly linking ganglioside metabolism with APP processing and Aß generation. A central aspect of this homeostatic control is the reduction of GD3S activity via an Aß-GM3 complex and AICD-mediated repression of GD3S transcription.

From brain to food: analysis of phosphatidylcholins, lyso-phosphatidylcholins and phosphatidylcholin-plasmalogens derivates in Alzheimer's disease human post mortem brains and mice model via mass spectrometry.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular senile plaques mainly consisting of Aß, a 40-42 amino acid long peptide, and intracellular neurofibrillary tangles, accompanied by an excessive loss of synapses. Recently evidence accumulated that nutrition, especially polyunsaturated fatty acids, influences AD pathogenesis. Especially mid-life food habits with the consumption of specific fatty acids (FA) appear to influence the disease risk. The timely separation between food intake and disease makes a direct correlation with detailed analysis of eating habits combined with accurate food analysis nearly unattainable. A possible solution to circumvent these difficulties is to investigate the FA composition in human post mortem brain. In this study we focused on the main phospholipids phosphatidylcholin (PC), phosphatidylcholin-plasmalogen (PC-PL) and lyso-phosphatidylcholin (lyso-PC) in AD brains compared to control brains. Frontal cortices, temporal cortices and cerebellum of 30 AD (mean 78 years) and 14 control aged matched brains (mean 77.4 years) as well as APP transgenic mice compared to control mice were analyzed using an AB Sciex 4000 Qtrap mass spectrometer utilizing a FIA MS/MS method. PC, PC-PL and lyso-PC metabolites were analyzed in respect to saturation level and FA composition. As expected, the majority of the lipid species showed no significant differences, but interestingly a few species revealed a highly significant reduction in AD brains. These FAs are potential candidates for further food analysis in respect to AD pathology. Additionally, we show that the method applied with multiple reaction monitoring (MRM) used for this study is suitable for semi quantitative analysis of small amounts (10 µl) of brain tissue.

Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease.

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aß), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipid de novo synthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic AD postmortem brains, suggesting that SPT is involved in AD pathology.