Journal of Parkinsons disease and Alzheimers disease

Review Article

Altered Cholesterol Intracellular Trafficking and the Development of Pathological Hallmarks of Sporadic AD

Xuesong Chen*, Liang Hui, Mahmoud L. Soliman and Jonathan D. Geiger

  • Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA

*Address for Correspondence: Dr. Xuesong Chen, Ph.D., Department of Basic Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, 504 Hamline Street, Grand Forks, North Dakota-58203, USA, Tel: (701)777-0919; Fax: (701)777-0387; E-mail: xuesong.chen@med.und.edu
 
Citation: Chen X, Hui L, Soliman ML, Geiger JD. Altered Cholesterol Intracellular Trafficking and the Development of Pathological Hallmarks of Sporadic AD. J Parkinsons Dis Alzheimer Dis. 2014;1(1): 8.
 
Copyright © 2014 Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
 
Journal of Parkinson’s disease and Alzheimer's disease | ISSN: 2376-922X | Volume: 1, Issue: 1
 
Submission: 19 September 2014 | Accepted: 24 October 2014 | Published: 27 October 2014

Abstract

Compared to the rare familial early onset Alzheimer’s disease (AD) that results from gene mutations in AbPP and presenilin-1, the pathogenesis of sporadic AD is much more complex and is believed to result from complex interactions between nutritional, environmental, epigenetic and genetic factors. Among those factors, the presence APOE4 is still the single strongest genetic risk factor for sporadic AD. However, the exact underlying mechanism whereby apoE4 contributes to the pathogenesis of sporadic AD remains unclear. Here, we discuss how altered cholesterol intracellular trafficking as a result of apoE4 might contribute to the development of pathological hallmarks of AD including brain deposition of amyloid beta (Ab), neurofibrillary tangles, and synaptic dysfunction.

Keywords

ApoE4; Cholesterol; Alzheimer’s disease; Niemann-Pick type C disease

Introduction

Alzheimer’s disease (AD), the most common neurodegenerative disorder of old age, is characterized clinically by a progressive decline in cognitive function and pathologically by loss of neurons, disturbed synaptic integrity, and the presence of amyloid plaques composed of amyloid beta (Aβ) protein and neurofibrillary tangles composed ofhyperphosphorylated tau [1,2]. Although gene mutations in AβPP and presenilin-1 can lead to rare familial early onset AD [3], the pathogenic mechanisms responsible for sporadic AD, the major form of AD, have not yet been elucidated. It is believed that the pathogenesis of sporadic AD results from complex interactions between nutritional, environmental, epigenetic and genetic factors [4]. Central among the factors involved in AD pathogenesis might be the presence of the APOE4 allele, the single strongest genetic risk factor for sporadic AD [5-8]. Although several hypotheses (Aβ-dependent and Aβ- independent) have been proposed [9-12], the exact underlying mechanisms whereby apoE4 contributes to the pathogenesis of AD remain unclear. Here, we discuss how altered cholesterol intracellular trafficking as a result of apoE4 might contribute to the development of pathological hallmarks of AD including brain deposition of Aβ, neurofibrillary tangles, and synaptic dysfunction.


ApoE4 and Altered Cholesterol Intracellular Trafficking

Brain is the most cholesterol rich organ in the body and contains about 20% of the body’s total cholesterol. About 70% of brain cholesterol lies in the myelin sheaths of oligodendroglia and membranes of astrocytes; cholesterol in neurons make up the rest [13,14]. In contrast to plasma cholesterol, essentially all cholesterol in the brain is unesterified cholesterol [13]. Such unesterified cholesterol is of particular importance to neurons, because neurons are extraordinarily polarized cells with extensive processes thatrequire constant membrane trafficking and free cholesterol recycling to maintain physiologically important neuronal functions [14,15]. As such, as an essential component of cellular membranes, cholesterol helps maintain such physiologically important neuronal functions as neurotransmitter release, neurite outgrowth, and synaptic plasticity [16-18].

Because the blood-brain barrier (BBB) restricts plasma lipoproteins from entering brain parenchyma, brain cholesterol is almost completely dependent on in situ synthesis of apoE-cholesterol by astrocytes [19]. Although the structure and composition of apoEcholesterol in brain parenchyma is not known, it is estimated that apoE-cholesterol synthesized in situ in brain is a discoidal shaped HDL-like particle composed of phospholipids and unesterified cholesterol [20,21]. Such HDL-like apoE-cholesterol supplies the neuronal need of cholesterol via receptor-mediated endocytosis (Figure 1), a process where lipoproteins bound to their receptors are internalized, transported to endolysosomes, hydrolyzed to free cholesterol, and from where free cholesterol is transported to various intracellular compartments (ER, Golgi) or plasma membrane via a mechanism involving the Niemann-Pick type C (NPC) proteins type-1 (NPC1) and -2 (NPC2) proteins [22-24]. To accommodate the neuronal need for cholesterol, a large number of receptors for cholesterol uptake, including low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), LDLR related protein-1 (LRP-1), apoE receptor, and sorting protein-related receptor containing LDLR class A repeats (sorLA-1), are highly expressed on neurons [9,25-27].


JPA-14-0002-thumbFig1


Figure 1: Cholesterol homeostasis in brain. Brain cholesterol is almost completely dependent on in situ synthesis of HDL-like apoE-cholesterol by astrocytes. Such HDL-like apoE-cholesterol supplies the neuronal need of cholesterol via receptor-mediated endocytosis, a process where apoE-cholesterol bound to their receptors are internalized, transported to endolysosomes, hydrolyzed to free cholesterol, and from where free cholesterol is transported to various intracellular compartments (ER, Golgi) or plasma membrane via a mechanism involving the Niemann-Pick type C proteins type-1 and -2 proteins.


 Similar to the role of plasma HDL [28,29], brain apoE-cholesterol may mediate cholesterol recycling and cholesterol efflux [20]; two functions of great importance for fundamental physiological functions of neurons. In addition, neurons are extraordinarily polarized cells with extensive processes that require constant membrane trafficking to maintain a variety of physiologically important neuronal functions such as neurotransmitter release, neurite outgrowth, and synaptic plasticity. Indeed, apoE is important for the regulation of synapse formation, plasticity and repair [30,31], and apoE cholesterol, the natural source of neuronal cholesterol, is neuroprotective [32,33].

There are three apoE isoforms and their amino acid differences are restricted to residues 112 and 158; apoE2 (Cys112, Cys158), apoE3 (Cys112, Arg158), and apoE4 (Arg112, Arg158). Such sequence differences affect the structure of apoE isoforms and influence their ability to bind lipids and receptors [11,34,35], with apoE4 having the highest binding affinity for LDLR and lipids, whereas apoE2 having the lowest binding affinity [36,37]. APOE4 is still the single strongest genetic risk factor for sporadic AD [5-8], whereas the APOE2 allele exerts protective effects against sporadic AD [38]. Associations between cholesterol and apoE isoforms can result in drastic differences in endocytic trafficking [39], with up to 87% of the intraneuronal apoE4 being co-localized with the lysosomal marker whereas only 9% of the apoE3 being co-localized. Indeed, apoE4 is associated with impaired cholesterol recycling, and such impaired recycling of cholesterol can lead to the accumulation of cholesterol in endolysosomes and reduced cholesterol recycling back to ER, Golgi and plasma membranes [37,40,41].

These apoE4-associated changes in cholesterol intracellular trafficking are similar, albeit less severe, to Niemann-Pick type C disease; a lysosomal lipid storage disorder caused by gene mutations in either the NPC1 or NPC2, both of which bind to cholesterol and act in tandem in late endosomes and/or lysosomes to mediate the egress of unesterified cholesterol derived from endocytosed lipoproteins [42]. In Niemann-Pick type C disease, the accumulation of cholesterol in lysosomes results in reduced recycling of cholesterol back to ER, Golgi, and plasma membranes thus leading to cholesterol deficiency at sites where it is needed for membrane repair, neurite outgrowth, and synaptic plasticity [30,31]. Moreover, endolysosome accumulation of cholesterol leads to endolysosome dysfunction, which contributes directly to the development of pathological hallmarks of AD including Aβ deposition [43], formation of neurofibrillary tangles [44], and synaptic and neuronal loss [45]. Thus, we hypothesize that apoE4 could contribute to the development of these pathological hallmarks of AD by disturbing cholesterol intracellular trafficking in a similar way as that of Niemann-Pick type C disease (Figure 2).


JPA-14-0002-thumbFig2


Figure 2: ApoE4-induced cholesterol dyshomeostasis. ApoE-cholesterol is up-taken by neurons via receptor-mediated endocytosis with the assistance of LDLRs. Different apoE isoforms have different affinities for lipids and receptors for cholesterol uptake, and the associations between cholesterol and different apoE can result in drastic differences in endocytic trafficking and distribution of cholesterol in neurons. ApoE4 could lead to impaired recycling of cholesterol back to ER, Golgi and plasma membranes, where cholesterol is needed for membrane repair, neurite outgrowth, and synaptic plasticity. In addition, apoE4 could increase accumulation of cholesterol in endolysosomes thus disturbing endolysosome function.
 

ApoE4 and increased Aβ generation

Brain deposition of Aβ is a pathological hallmark of AD. Intracellular accumulation and extracellular deposition of Aβ starts with specific proteolytic cleavage of AβPP, a ubiquitously expressed type-I transmembrane protein with largely uncharacterized physiological functions. AβPP is synthesized in the endoplasmic reticulum and it is transported to the Golgi/trans-Golgi network apparatus where it undergoes posttranslational modifications and maturation. Once inserted into plasma membranes via secretory vesicles, AβPP can traffic into endosomes via clathrin-dependent endocytosis whereupon it can either be recycled back to the cell surface or it is delivered to lysosomes for possible degradation [46,47]. Endolysosomes appear to play a critical role in amyloidogenic processing of AβPP [46,48,49] in part because this is where the ratelimiting enzyme BACE-1 and γ-secretase are almost exclusively located. In addition, the acidic environment of endolysosomes is favorable for amyloidogenic metabolism of AβPP [50-53]. Amyloidogenesis of endosome-derived Aβ is further influenced by Aβ degradation catalyzed by lysosome-resident cathepsins [54]. Once formed, Aβ can accumulate in endolysosomes as intraneuronal Aβ or it can undergo exocytotic release into extracellular spaces where diffuse Aβ plaques can form. Thus, Aβ generation can be enhanced by such factors as those that promote AβPP internalization [55], those that enhance protein levels and/or activities of BACE-1 and/or γ-secretase, those that prevent AβPP recycling back to the cell surface [56], and those that impair Aβ degradation in lysosomes [57].

Among these mechanisms, apoE4 could alter endocytic trafficking of AβPP [58], such an effect might result from the fact that apoE isoforms has different binding affinities to apoE receptors that mediates cholesterol uptake [59]. On one hand, apoE4 could promote AβPP internalization, because receptors for apoE uptake such as LRP1 and LRP10 have been shown to interact with AβPP and affect AβPP internalization [46,60,61]. On the other hand, apoE4 may have lower binding affinity to sorLA1, an apoE receptor that mediates the recycling of internalized AβPP from endosome back to Golgi and/or plasma membrane [62,63]. As a result, apoE4 may impair recycling of internalized AβPP, thus leading to accumulation of AβPP in endosome; the site where amyloidogenic processing of AβPP occurs [46,48,49]. Another mechanism whereby apoE4 promotes Aβ generation might result from endolysosome dysfunction, which has been elegantly brought out by studies from Nixon, Annaert, and others [64-68]. Indeed, it has been shown that apoE4 could lead to the accumulation of cholesterol in endolysosomes [37,40,41], an effect that could impair lysosomal degradation ability as occurs in Niemann- Pick type C disease [43]. Such apoE4-induced endolysosome cholesterol accumulation and endolysosome dysfunction could, on one hand, promote the interaction of APP with BACE-1 in endosome [69] thus enhancing Aβ generation in endosomes, and on the other hand impaire Aβ degradation in lysosomes thus leading to increased intraneuronal accumulation of Aβ [70]. In support, altered structure of endolysosome, an indication of endolysosome dysfunction, and intraneuronal accumulation of Aβ in endosomes correlate with apoE4 genotype [69-72]. Thus, by disturbing AβPP endocytic trafficking and/or impairing endolysosome function, apoE4 leads intraneuronal accumulation of Aβ (Figure 3).


JPA-14-0002-thumbFig3



Figure 3: ApoE4-cholesterol contributes to the development of AD pathology. ApoE4 could promote AβPP internalization or impair recycling of internalized AβPP, and thus to leads enhanced amyloidgenic processing of AβPP in endosome, the site where BACE-1 and γ-secretase are almost exclusively located and active in the acidic environment. Another mechanism whereby apoE4 promotes Aβ generation might result from apoE4-induced endolysosome cholesterol accumulation and endolysosome dysfunction, which could enhance Aβ generation in endosomes and inhibit Aβ degradation in lysosomes. Because hyperphosphorylated tau can be degraded in autophagosomes-lysosomes, apoE4-induced cholesterol accumulation in endolysosome and subsequent endolysosome dysfunction could impair tau degradation in autophagosome-lysosomes, thus leading to increased accumulation of hyperphosphorylated tau and the development of neurofibrillary tangle.
 

ApoE4 and the Formation of Neurofibrillary Tangle

Neurofibrillary tangle, composed of hyperphosphorylated tau, is another pathological hallmarks of AD. Besides the role of enhanced tau phosphorylation, as induced by apoE4 via apoE receptors and downstream signaling, in the development of neurofibrillary tangles [73-75], apoE4 could lead to the development of neurofibrillary tangle by altering intracellular cholesterol trafficking. As mentioned earlier, apoE4 could lead to the accumulation of cholesterol in endolysosomes [37,40,41], an effect that could impair lysosome degradation. In support, altered structure of endolysosome, which indicates endolysosome dysfunction, correlates with apoE4 genotype [71,72]. Because tau and hyperphosphorylated tau can be degraded by cathepsin D in autophagosomes-lysosomes [76-80], impaired lysosome degradation could lead to the development of neurofibrillary tangle. In support, increased accumulation of cholesterol in lysosomes and subsequent lysosome dysfunction has been linked to the development of neurofibrillary tangle in brains of patients with Niemann-Pick type C disease [81-86]. Thus, apoE4 could lead to the formation of neurofibrillary tangle by altering cholesterol intracellular trafficking and subsequent endolysosome dysfunction (Figure 3).

ApoE4 and Synaptic Dysfucntion

Synaptic dysfunction is the pathological hallmark of AD that correlates best with dementia [87,88]. Neurons are extraordinarily polarized cells with extensive processes that require constant membrane trafficking and cholesterol recycling to maintain a variety of physiologically important neuronal functions such as neurotransmitter release, neurite outgrowth, and synaptic plasticity. Indeed, apoE is important for the regulation of synapse formation, plasticity and repair [30,31]. Accordingly, impaired cholesterol recycling associated with apoE4 could lead to increased accumulation of cholesterol in endolysosome and reduced cholesterol recycling back and plasma membranes [37,40,41], where it is needed for membrane repair, neurite outgrowth, and synaptic plasticity. As such, impaired apoE4 recycling could lead to synaptic dysfunction [40,89]. Another mechanism whereby apoE4 could lead to synaptic dysfunction might result from the fact that apoE4 could lead to increased accumulation of cholesterol in endolysosome [37,40,41] and subsequent endolysosome dysfunction as occurs in Niemann-Pick type C disease [43]. In support, endolysosome dysfunction has been linked to synaptic pathology in AD brain [90,91] and deacidification of endolysosomes with chloroquine results in synaptic dysfunction and synaptic loss [92-94]. Thus, by impairing cholesterol recycling and disturbing endolysosome function, apoE4 could contribute to the development of synaptic dysfunction. Alternatively, apoE4 could contribute to synaptic dysfunction in AD via its effects on Aβ and tau pathologies [95-97].

Potential Therapeutic Strategies

Given the importance of altered cholesterol homeostasis in thepathogenesis of AD, cholesterol lowering drugs have been proposed as potential strategy for the treatment and/or prevention of AD [98]. However, the use of statins, a class of hydroxylmethylglutaryl-CoA (HMG-CoA) reductase inhibitors that block cholesterol biosynthesis thus lowering cholesterol levels, may not provide beneficial effects for AD. Because chronic use of statins results in over-expression of LDLRs and enhanced cholesterol uptake [99], and such an effect could increase the cholesterol burden in endolysosomes and worsen endolysosome dysfunction. Thus, it is not surprising that statins have no beneficial effects on Niemann-Pick type C disease [100,101], and that recent data from randomized clinical trials indicates that statins have little or no beneficial effects against AD [102-106] and in some cases statins result in adverse effects on memory and cognitions [107-110].

Thus, a more appropriate way in dealing with apoE4-associated disturbance in cholesterol homeostasis might be reducing cholesterol burden in endolysosomes. One such way is to promote cholesterol recycling, and the target protein might be SorLA, (also known as SORL1 or LR11), a mosaic member of LDL receptor family that could mediate protein retrograde transport from endosome to Golgi [27]. Besides its role in binding apoE cholesterol, SorLA, a Vps10p domain-containing receptor, is known to interact with APP and mediate its retrograde transport from endosome to Golgi [62,63,111]. Thus, over-expressing SorLA prevents amyloidogenic processing ofAPP in endolysosomes [63]. The other way in reducing cholesterol burden in endolysosome might be extracting endolysosome cholesterol into cytosol with cyclodextrin for further clearance [112]. Another way in reducing cholesterol burden in endolysosome might be suppressing cholesterol endocytosis and promoting cholesterol efflux, for instance, by using histone deacetylase inhibitors [113,114] or promoting lysosome exocytosis [115,116].

Besides direct targeting at cholesterol homeostasis, enhancing lysosome function represents another important strategy, which is recently reviewed by Nixon [117]. This strategy includes autophagy induction by inhibiting mTORC1 with rapamycin [118] or by activating AMPK with resveratrol [119], enhancing lysosome biogenesis by activating transcription factor EB [120,121], a master regulator of endolysosome biogenesis and function [122], and improving lysosome function by restoring lysosomal acidification [123].

Conclusion

ApoE4-associated alteration in cholesterol intracellular trafficking could lead to increased cholesterol accumulation in endolysosome and decreased recycling of cholesterol back to plasma membrane, a set of conditions share striking similarity (albeit less severely) to lysosomal lipid storage disorders as seen in Niemann-Pick type C disease. We propose that such an effect plays a key role in the apoE4- induced pathological hallmarks of sporadic AD including brain deposition of Aβ, neurofibrillary tangles, and disturbed synaptic integrity, a hypothesis that requires further evaluation. It should be noted that having one or two copies of the APOE4 gene does not mean a person will necessarily develop AD. Thus, other factors such as nutritional, environmental, epigenetic and genetic factors and their complex interactions are involved in the pathogenesis of sporadic AD [4].

Acknowledgements

The authors acknowledge grant support from R01MH100972 and R21AG103329.

References

  1. Glenner GG and Wong CW (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120: 885-890.
  2. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, et al. (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83: 4913-4917.
  3. Goate A and Hardy J (2011) Twenty years of Alzheimer's disease-causing mutations. J Neurochem 120 Suppl 1: 3-8.
  4. Reitz C, Brayne C, and Mayeux R (2011) Epidemiology of Alzheimer disease. Nat Rev Neurol 7: 137-152.
  5. Reitz C, Rogaeva E, Foroud T, Farrer LA (2011) Genetics and genomics of late-onset Alzheimer's disease and its endophenotypes. Int J Alzheimers Dis 2011: 284728.
  6. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, et al. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278: 1349-1356.
  7. 7. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, et al. (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41: 1088-1093.
  8. Lambert JC, Heath S, Even G, Campion D, Sleegers K, et al. (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41: 10949.
  9. Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9: 106-118.
  10. Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, et al. (2013) ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci U S A 110: E1807-16.
  11. Kanekiyo T, Xu H, Bu G (2014) ApoE and Abeta in Alzheimer's disease: accidental encounters or partners? Neuron 81: 740-754.
  12. Tai LM, Mehra S, Shete V, Estus S, Rebeck GW, et al. (2014) Soluble apoE/Abeta complex: mechanism and therapeutic target for APOE4-induced AD risk. Mol Neurodegener 9: 2.
  13. Bjorkhem I , Meaney S (2004) Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 24: 806-815.
  14. Orth M , Bellosta S (2012) Cholesterol: its regulation and role in central nervous system disorders. Cholesterol 292598.
  15. Vance JE, Hayashi H, Karten B (2005) Cholesterol homeostasis in neurons and glial cells. Semin Cell Dev Biol 16: 193-212.
  16. Linetti A, Fratangeli A, Taverna E, Valnegri P, Francolini M, et al. (2010) Cholesterol reduction impairs exocytosis of synaptic vesicles. J Cell Sci 123: 595-605.
  17. Koudinov AR, Koudinova NV (2001) Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J 15: 1858-1860.
  18. Funfschilling U, Jockusch WJ, Sivakumar N, Mobius W, Corthals K, et al. (2012) Critical time window of neuronal cholesterol synthesis during neurite outgrowth. J Neurosci 32: 7632-7645.
  19. Nieweg K, Schaller H, Pfrieger FW (2009) Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem 109: 125-134.
  20. de Chaves EP, Narayanaswami V (2008) Apolipoprotein E and cholesterol in aging and disease in the brain. Future Lipidol 3: 505-530.
  21. Vance JE (2012) Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech 5: 746-755.
  22. Maxfield FR, Tabas I (2005) Role of cholesterol and lipid organization in disease. Nature 438: 612-621.
  23. Vance JE, Karten B, Hayashi H (2006) Lipid dynamics in neurons. Biochem Soc Trans 34: 399-403.
  24. Sleat DE, Wiseman JA, El-Banna M, Price SM, Verot L, et al. (2004) Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci U S A 101: 5886-5891.
  25. Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, et al. (1998) The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease. Brain Res Brain Res Rev 27: 119-142.
  26. Dietschy JM (2009) Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 390: 287-293.
  27. Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2: a006312.
  28. Mahley RW, Huang Y, Weisgraber KH (2006) Putting cholesterol in its place: apoE and reverse cholesterol transport. J Clin Invest 116: 1226-1229.
  29. Matsuura F, Wang N, Chen W, Jiang XC, Tall AR (2006) HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. J Clin Invest 116: 1435-1442.
  30. Rebeck GW, Kindy M, LaDu MJ (2002) Apolipoprotein E and Alzheimer's disease: the protective effects of ApoE2 and E3. J Alzheimers Dis 4: 145-154.
  31. Poirier J (2008) Apolipoprotein E represents a potent gene-based therapeutic target for the treatment of sporadic Alzheimer's disease. Alzheimers Dement 4: S91-S97.
  32. Hayashi H, Eguchi Y, Fukuchi-Nakaishi Y, Takeya M, Nakagata N, et al. (2012) A potential neuroprotective role of apolipoprotein E-containing lipoproteins through low density lipoprotein receptor-related protein 1 in normal tension glaucoma. J Biol Chem 287: 25395-25406.
  33. Hayashi H, Campenot RB, Vance DE, Vance JE (2007) Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1. J Neurosci 27: 1933-1941.
  34. Garai K, Baban B, Frieden C (2011) Self-association and stability of the ApoE isoforms at low pH: implications for ApoE-lipid interactions. Biochem 50: 6356-6364.
  35. Yamamoto T, Choi HW, Ryan RO (2008) Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor. Anal Biochem 372: 222-226.
  36. Weisgraber KH (1994) Apolipoprotein E: structure-function relationships. Adv Protein Chem 45: 249-302.
  37. Gong JS, Morita SY, Kobayashi M, Handa T, Fujita SC, et al. (2007) Novel action of apolipoprotein E (ApoE):
  38. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, et al. (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7: 180-184.
  39. DeKroon RM, Armati PJ (2001) The endosomal trafficking of apolipoprotein E3 and E4 in cultured human brain neurons and astrocytes. Neurobiol Dis 8: 78-89.
  40. Chen Y, Durakoglugil MS, Xian X, Herz J (2010) ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A 107: 12011-12016.
  41. Heeren J, Grewal T, Laatsch A, Becker N, Rinninger F, et al. (2004) Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation. J Biol Chem 279: 55483-55492.
  42. Pacheco CD, Lieberman AP (2008) The pathogenesis of Niemann-Pick type C disease: a role for autophagy? Expert Rev Mol Med 10: e26.
  43. Jin LW, Shie FS, Maezawa I, Vincent I, Bird T (2004) Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am J Pathol 164: 975-985.
  44. Suzuki K, Parker CC, Pentchev PG, Katz D, Ghetti B, et al. (1995) Neurofibrillary tangles in Niemann-Pick disease type C. Acta Neuropathol 89: 227-238.
  45. Pressey SN, Smith DA, Wong AM, Platt FM, Cooper JD (2012) Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice. Neurobiol Dis 45: 1086-1100.
  46. Jiang S, Li Y, Zhang X, Bu G, Xu H, et al. ( 2014) Trafficking regulation of proteins in Alzheimer's disease. Mol Neurodegener 9: 6.
  47. Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2: a006270.
  48. Rajendran L, Annaert W (2012) Membrane trafficking pathways in Alzheimer's disease. Traffic 13: 759-770.
  49. Morel E, Chamoun Z, Lasiecka ZM, Chan RB, Williamson RL, et al. (2013) Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun 4: 2250.
  50. Nixon RA (2005) Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol Aging 26: 373-382.
  51. Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, et al. (2008) Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science 320: 520-523.
  52. Sannerud R, Declerck I, Peric A, Raemaekers T, Menendez G, et al (2011) ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci U S A 108: E559-568.
  53. Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, et al. (2008) Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production. Mol Cell Biol 28: 3663-3671.
  54. Miners JS, Barua N, Kehoe PG, Gill S, Love S (2011) Aβ -degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol 70: 944-959.
  55. Grbovic OM, Mathews PM, Jiang Y, Schmidt SD, Dinakar R, et al. (2003) Rab5-stimulated up-regulation of the endocytic pathway increases intracellular beta-cleaved amyloid precursor protein carboxyl-terminal fragment levels and Abeta production. J Biol Chem 278: 31261-31268.
  56. Ma QL, Galasko DR, Ringman JM, Vinters HV, Edland SD, et al. (2009) Reduction of SorLA/LR11, a sorting protein limiting beta-amyloid production, in Alzheimer disease cerebrospinal fluid. Arch Neurol 66: 448-457.
  57. Torres M, Jimenez S, Sanchez-Varo R, Navarro V, Trujillo-Estrada L, et al. (2012) Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus. Mol Neurodegener 7: 59.
  58. Ye S, Huang Y, Mullendorff K, Dong L, Giedt G, et al. (2005) Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proc Natl Acad Sci U S A 102: 18700-18705.
  59. Bachmeier C, Shackleton B, Ojo J, Paris D, Mullan M, et al. ( 2014) Apolipoprotein E Isoform-Specific Effects on Lipoprotein Receptor Processing. Neuromolecular Med.
  60. Brodeur J, Theriault C, Lessard-Beaudoin M, Marcil A, Dahan S, et al. (2012) LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer's disease. Mol Neurodegener 7: 31.
  61. Yoon IS, Chen E, Busse T, Repetto E, Lakshmana MK, et al. (2007) Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway. FASEB J 21: 2742-2752.
  62. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, et al. (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 102: 13461-13466.
  63. Willnow TE, Andersen OM (2013) Sorting receptor SORLA--a trafficking path to avoid Alzheimer disease. J Cell Sci 126: 2751-2760.
  64. Li J, Kanekiyo T, Shinohara M, Zhang Y, LaDu MJ, et al. (2012) Differential regulation of amyloid-beta endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. J Biol Chem 287: 44593-44601.
  65. Coen K, Flannagan RS, Baron S, Carraro-Lacroix LR, Wang D, et al. (2012) Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J Cell Biol 198: p23-35.
  66. McBrayer M, Nixon RA (2013) Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime. Biochem Soc Trans 41: 1495-1502.
  67. Orr ME, Oddo S (2013) Autophagic/lysosomal dysfunction in Alzheimer's disease. Alzheimers Res Ther 5: 53.
  68. Nixon RA (2004) Niemann-Pick Type C disease and Alzheimer's disease: the APP-endosome connection fattens up. Am J Pathol 164: 757-761.
  69. Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, et al. (2013) Integrative genomics identifies APOE epsilon4 effectors in Alzheimer's disease. Nature 500: 45-50.
  70. Zhao W, Dumanis SB, Tamboli IY, Rodriguez GA, Jo Ladu M, et al. (2014) Human APOE genotype affects intraneuronal Abeta1-42 accumulation in a lentiviral gene transfer model. Hum Mol Genet 23: 1365-1375.
  71. Christensen DZ, Schneider-Axmann T, Lucassen PJ, Bayer TA, Wirths O (2010) Accumulation of intraneuronal Abeta correlates with ApoE4 genotype. Acta Neuropathol 119: 555-566.
  72. Cataldo AM, Petanceska S, Terio NB, Peterhoff CM, Durham R, et al. (2004) Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome. Neurobiol Aging 25: 1263-1272.
  73. Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, et al. (2004) Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci 24: 2527-2534.
  74. Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Y (2004) Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J Biol Chem 279: 44795-44801.
  75. Liraz O, Boehm-Cagan A, Michaelson DM (2013) ApoE4 induces Abeta42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice. Mol Neurodegener 8: 16.
  76. Oyama F, Murakami N, Ihara Y (1998) Chloroquine myopathy suggests that tau is degraded in lysosomes: implication for the formation of paired helical filaments in Alzheimer's disease. Neurosci Res 31: 1-8.
  77. Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, et al. (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18: 4153-4170.
  78. Hamano T, Gendron TF, Causevic E, Yen SH, Lin WL, et al. (2008) Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur J Neurosci 27: 1119-1130.
  79. Kenessey A, Nacharaju P, Ko LW, Yen SH (1997) Degradation of tau by lysosomal enzyme cathepsin D: implication for Alzheimer neurofibrillary degeneration. J Neurochem 69: 2026-2038.
  80. Chesser AS, Pritchard SM, Johnson GV (2013) Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease. Front Neurol 4: 122.
  81. Distl R, Treiber-Held S, Albert F, Meske V, Harzer K, et al. (2003) Cholesterol storage and tau pathology in Niemann-Pick type C disease in the brain. J Pathol 200: 104-111.
  82. Bi X, Liao G (2007) Autophagic-lysosomal dysfunction and neurodegeneration in Niemann-Pick Type C mice: lipid starvation or indigestion? Autophagy 3: 646-648.
  83. Liao G, Yao Y, Liu J, Yu Z, Cheung S, et al. (2007) Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1 -/- mouse brain. Am J Pathol 171: 962-975.nd cardiovascular disease. Curr Vasc Pharmacol 5: 93-102.
  84. Vance JE (2006) Lipid imbalance in the neurological disorder, Niemann-Pick C disease. FEBS Lett 580: 5518-5524.
  85. Bu B, Li J, Davies P, Vincent I (2002) Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model. J Neurosci 22: 6515-6525.
  86. Sawamura N, Gong JS, Garver WS, Heidenreich RA, Ninomiya H, et al. (2001) Site-specific phosphorylation of tau accompanied by activation of mitogen-activated protein kinase (MAPK) in brains of Niemann-Pick type C mice. J Biol Chem 276: 10314-10319.
  87. Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298: 789-791.
  88. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, et al. (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30: 572-580.
  89. Lane-Donovan C, Philips GT, Herz J (2014) More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration. Neuron 83: 771-787.
  90. Callahan LM, Vaules WA, Coleman PD (1999) Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J Neuropathol Exp Neurol 58: 275-287.
  91. Bahr BA, Bendiske J (2002) The neuropathogenic contributions of lysosomal dysfunction. J Neurochem 83: 481-489.
  92. Bendiske J, Bahr BA (2003) Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis--an approach for slowing Alzheimer disease? J Neuropathol Exp Neurol 62: 451-463.
  93. Bendiske J, Caba E, Brown QB, Bahr BA (2002) Intracellular deposition, microtubule destabilization, and transport failure: an "early" pathogenic cascade leading to synaptic decline. J Neuropathol Exp Neurol 61: 640-650.
  94. Kanju PM, Parameshwaran K, Vaithianathan T, Sims CM, Huggins K, et al. (2007) Lysosomal dysfunction produces distinct alterations in synaptic alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid and N-methyl-D-aspartate receptor currents in hippocampus. J Neuropathol Exp Neurol 66: 779-788.
  95. Crimins JL, Pooler A, Polydoro M, Luebke JI, Spires-Jones TL (2013) The intersection of amyloid beta and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer's disease. Ageing Res Rev 12: 757-763.
  96. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Clos AL, Jackson GR, et al. (2011) Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol Neurodegener 6: 39.
  97. Crespo-Biel N, Theunis C, Van Leuven F (2012) Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease. Int J Alzheimers Dis 2012: 251426.
  98. Kandiah N, Feldman HH (2009) Therapeutic potential of statins in Alzheimer's disease. J Neurol Sci 283: 230-234.
  99. Goldstein JL, Brown MS (2009) The LDL receptor. Arterioscler Thromb Vasc Biol 29: 431-438.
  100. Patterson MC, Di Bisceglie AM, Higgins JJ, Abel RB, Schiffmann R, et al. (1993) The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C. Neurology 43: 61-64.
  101. Madra M, Sturley SL (2010) Niemann-Pick type C pathogenesis and treatment: from statins to sugars. Clin Lipidol 5: 387-395.
  102. McGuinness B, Craig D, Bullock R, Malouf R, Passmore P (2014) Statins for the treatment of dementia. Cochrane Database Syst Rev 7: CD007514.
  103. Silva T, Teixeira J, Remiao F, Borges F (2013) Alzheimer's disease, cholesterol, and statins: the junctions of important metabolic pathways. Angew Chem Int Ed Engl 52: 1110-1121.
  104. Shinohara M, Sato N, Shimamura M, Kurinami H, Hamasaki T, et al. (2014) Possible modification of Alzheimer's disease by statins in midlife: interactions with genetic and non-genetic risk factors. Front Aging Neurosci 6: 71.
  105. Wong WB, Lin VW, Boudreau D, Devine EB (2013) Statins in the prevention of dementia and Alzheimer's disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol Drug Saf 22: 345-358.
  106. Kelley BJ, Glasser S (2014) Cognitive effects of statin medications. CNS Drugs 28: 411-419.
  107. Orsi A, Sherman O, Woldeselassie Z (2001) Simvastatin-associated memory loss. Pharmacotherapy 21: 767-769.
  108. Evans MA, Golomb BA (2009) Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy 29: 800-811.
  109. Harrison RW, Ashton CH (1994) Do cholesterol-lowering agents affect brain activity? A comparison of simvastatin, pravastatin, and placebo in healthy volunteers. Br J Clin Pharmacol 37: 231-236.
  110. Goldstein MR, Mascitelli L, Pezzetta F, Haan MN, Cramer C, et al. (2009) Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 72: 1190-1191.
  111. Caglayan S, Takagi-Niidome S, Liao F, Carlo AS, Schmidt V, et al. (2014) Lysosomal sorting of amyloid-beta by the SORLA receptor is impaired by a familial Alzheimer's disease mutation. Sci Transl Med 6: 223ra20.
  112. Yao J, Ho D, Calingasan NY, Pipalia NH, Lin MT, et al. (2012) Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J Exp Med 209: 2501-2513.
  113. Nunes MJ, Moutinho M, Gama MJ, Rodrigues CM, Rodrigues E (2013) Histone deacetylase inhibition decreases cholesterol levels in neuronal cells by modulating key genes in cholesterol synthesis, uptake and efflux. PLoS One 8: e53394.
  114. Simoes-Pires C, Zwick V, Nurisso A, Schenker E, Carrupt PA, et al. (2013) HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs? Mol Neurodegener 8: 7.
  115. Yuyama K, Sun H, Mitsutake S, Igarashi Y (2012) Sphingolipid-modulated exosome secretion promotes clearance of amyloid-beta by microglia. J Biol Chem 287: 10977-10989.
  116. Samie MA, Xu H (2014) Lysosomal exocytosis and lipid storage disorders. J Lipid Res 55: 995-1009.
  117. Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19: 983-997.
  118. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, et al. (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One 5: e9979.
  119. Vingtdeux V, Giliberto L, Zhao H, Chandakkar P, Wu Q, et al. (2010) AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J Biol Chem 285: 9100-9113.
  120. Polito VA, Li H, Martini-Stoica H, Wang B, Yang L, et al. (2014) Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med 6: 1142-1160.
  121. Xiao Q, Yan P, Ma X, Liu H, Perez R, et al. (2014) Enhancing astrocytic lysosome biogenesis facilitates Abeta clearance and attenuates amyloid plaque pathogenesis. J Neurosci 34: 9607-9620.
  122. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, et al. (2011) TFEB links autophagy to lysosomal biogenesis. Science 332: 1429-1433.
  123. Avrahami L, Farfara D, Shaham-Kol M, Vassar R, Frenkel D, et al. (2013) Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. J Biol Chem 288: 1295-1306.