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Cited by 226Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyCellular transport and secretion

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Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors

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Van Acker, Zoë P., Bretou, Marine, Annaert, Wim·2019·Molecular Neurodegeneration
DOI 10.1186/s13024-019-0323-7PMC PMC6547588
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Abstract

Increasing evidence supports that cellular dysregulations in the degradative routes contribute to the initiation and progression of neurodegenerative diseases, including Alzheimer's disease. Autophagy and endolysosomal homeostasis need to be maintained throughout life as they are major cellular mechanisms involved in both the production of toxic amyloid peptides and the clearance of misfolded or aggregated proteins. As such, alterations in endolysosomal and autophagic flux, as a measure of degradation activity in these routes or compartments, may directly impact as well on disease-related mechanisms such as amyloid-β clearance through the blood-brain-barrier and the interneuronal spreading of amyloid-β and/or Tau seeds, affecting synaptic function, plasticity and metabolism. The emerging of several genetic risk factors for late-onset Alzheimer's disease that are functionally related to endocytic transport regulation, including cholesterol metabolism and clearance, supports the notion that in particular the autophagy/lysosomal flux might become more vulnerable during ageing thereby contributing to disease onset. In this review we discuss our current knowledge of the risk genes APOE4, BIN1, CD2AP, PICALM, PLD3 and TREM2 and their impact on endolysosomal (dys)regulations in the light of late-onset Alzheimer's disease pathology.

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Figures

Fig. 1 Spatial regulation of non-amyloidogenic and amyloidogenic processing of APP. Dysregulated amyloid precursor protein (APP) trafficking and processing underlies the most prominent hallmark of disease in AD affected areas, represented by an abundance of Aβ soluble oligomers, fibrils and plaques. Non-amyloidogenic processing starts with APP shedding by ADAM10, mainly at the cell surface but as well in the trans-Golgi network [10]. Hereafter, the remaining carboxyterminal fragments (CTFs), C83, are processed by γ-secretase to produce harmless p3 peptides and an intracellular domain (inset a). In the amyloidogenic pathway (inset b for details), which occurs more dominantly in neurons, APP is cleaved first by BACE1 preferentially in endosomes. This endosomal encountering is spatially regulated as BACE1 and APP are found to follow distinct internalization itineraries, the former mediated through ARF6 and GGA3 [11]. C99 is further processed by γ-secretase in recycling and degradative endosomes. It is first cut at position 48 or 49 of the Aβ sequence (ε-cleavage), followed by a carboxypeptidase-like trimming every three amino acids. This results in the production of different Aβ peptides of which the longer ones, like Aβ42 and Aβ43, are more aggregation-prone. γ-Secretase assembly is thought to occur stepwise during ER-Golgi recycling [12]. Assembled PSEN1 complexes (PSEN1/γ) are active at the cell surface and in sorting/recycling endosomes, while PSEN2 complexes (PSEN2/γ) reside in late endosomes/lysosomes due to an aminoterminal sorting motif that selectively binds AP-1. PICALM may mediate internalization of PSEN1/γ, while CD2AP in neurons sorts APP into intraluminal vesicles of MVBs for degradation in lysosomes, instead of through secretase-mediated processing pathways. BIN1 intervenes in recycling BACE1 to the cell surface as well as to lysosomes. BACE1 and APP sorting between distinct compartments involves several other sorting proteins and adaptor complexes of which some are depicted in this figure: such as GGA1, SNX17, retromer and SorLA
Fig. 1 Spatial regulation of non-amyloidogenic and amyloidogenic processing of APP. Dysregulated amyloid precursor protein (APP) trafficking and processing underlies the most prominent hallmark of disease in AD affected areas, represented by an abundance of Aβ soluble oligomers, fibrils and plaques. Non-amyloidogenic processing starts with APP shedding by ADAM10, mainly at the cell surface but as well in the trans-Golgi network [10]. Hereafter, the remaining carboxyterminal fragments (CTFs), C83, are processed by γ-secretase to produce harmless p3 peptides and an intracellular domain (inset a). In the amyloidogenic pathway (inset b for details), which occurs more dominantly in neurons, APP is cleaved first by BACE1 preferentially in endosomes. This endosomal encountering is spatially regulated as BACE1 and APP are found to follow distinct internalization itineraries, the former mediated through ARF6 and GGA3 [11]. C99 is further processed by γ-secretase in recycling and degradative endosomes. It is first cut at position 48 or 49 of the Aβ sequence (ε-cleavage), followed by a carboxypeptidase-like trimming every three amino acids. This results in the production of different Aβ peptides of which the longer ones, like Aβ42 and Aβ43, are more aggregation-prone. γ-Secretase assembly is thought to occur stepwise during ER-Golgi recycling [12]. Assembled PSEN1 complexes (PSEN1/γ) are active at the cell surface and in sorting/recycling endosomes, while PSEN2 complexes (PSEN2/γ) reside in late endosomes/lysosomes due to an aminoterminal sorting motif that selectively binds AP-1. PICALM may mediate internalization of PSEN1/γ, while CD2AP in neurons sorts APP into intraluminal vesicles of MVBs for degradation in lysosomes, instead of through secretase-mediated processing pathways. BIN1 intervenes in recycling BACE1 to the cell surface as well as to lysosomes. BACE1 and APP sorting between distinct compartments involves several other sorting proteins and adaptor complexes of which some are depicted in this figure: such as GGA1, SNX17, retromer and SorLACC BY · PubMed Central
Fig. 2 Alzheimer disease risk factors and associated cellular mechanisms. Schematic representation of the biological processes linked to the different proteins being linked to familial AD (red dots) and to an increased risk to develop LOAD (cyan dots). Still to be validated LOAD risk factors are indicated as grey dots. Edges denote protein-protein associations. The figure was generated in Cytoscape with the “String enrichment” plugin and completed with recent interactions from Pubmed articles
Fig. 2 Alzheimer disease risk factors and associated cellular mechanisms. Schematic representation of the biological processes linked to the different proteins being linked to familial AD (red dots) and to an increased risk to develop LOAD (cyan dots). Still to be validated LOAD risk factors are indicated as grey dots. Edges denote protein-protein associations. The figure was generated in Cytoscape with the “String enrichment” plugin and completed with recent interactions from Pubmed articlesCC BY · PubMed Central
Fig. 3 Intrinsic and extrinsic factors dysregulating the endolysosomal flux promote progression to EOAD and LOAD, respectively. APP proteolysis is dysregulated in AD, as shown for instance for familial/early onset AD-associated mutations in PSEN genes. FAD-PSEN2 and some -PSEN1 mutations favor a late-endosomal and lysosomal localization of the respective γ-secretase complexes, driving an increased processing of APP into Aβ peptides. Other PSEN1 and PSEN2 FAD mutations shift the intrinsic cleavage functions of the complex, generating more Aβ42 rather than Aβ40. LOAD risk factors, on the other hand, entail the not-optimal working of different cellular mechanisms, e.g. the endolysosomal flux, making dysregulations to be build-up until they also start to impact other mechanisms. Hence, an elevation in the intracellular Aβ pools can originate from two factors: intrinsic ones (mutations linked with APP processing enzymes) and extrinsic ones (variants linked to a dysfunction or lower flux in the endolysosomal system, e.g. trapping γ-secretases in endosomes). While the intrinsic mutations drive FAD/EOAD, the extrinsic variants cause an increased risk of developing LOAD. Both ultimately lead to the characteristic AD clinical phenotype and pathology
Fig. 3 Intrinsic and extrinsic factors dysregulating the endolysosomal flux promote progression to EOAD and LOAD, respectively. APP proteolysis is dysregulated in AD, as shown for instance for familial/early onset AD-associated mutations in PSEN genes. FAD-PSEN2 and some -PSEN1 mutations favor a late-endosomal and lysosomal localization of the respective γ-secretase complexes, driving an increased processing of APP into Aβ peptides. Other PSEN1 and PSEN2 FAD mutations shift the intrinsic cleavage functions of the complex, generating more Aβ42 rather than Aβ40. LOAD risk factors, on the other hand, entail the not-optimal working of different cellular mechanisms, e.g. the endolysosomal flux, making dysregulations to be build-up until they also start to impact other mechanisms. Hence, an elevation in the intracellular Aβ pools can originate from two factors: intrinsic ones (mutations linked with APP processing enzymes) and extrinsic ones (variants linked to a dysfunction or lower flux in the endolysosomal system, e.g. trapping γ-secretases in endosomes). While the intrinsic mutations drive FAD/EOAD, the extrinsic variants cause an increased risk of developing LOAD. Both ultimately lead to the characteristic AD clinical phenotype and pathologyCC BY · PubMed Central
Fig. 4 Role of PICALM in autophagy and the degradation of tau fibrils. The catabolic autophagy cascade engulfs cytoplasmic content such as dysfunctional organelles, aggregated proteins or peptides for degradation in lysosomes. Autophagy can be initiated through different upstream (metabolic) signals that converge into the activation of two protein complexes, the ULK complex (ATG13, ATG101, FIP200 and ULK1) and the VPS34 complex (Atg6, Atg14, VPS15 and VPS34). One of the first steps is the formation of the phagophore that recruits ubiquitinated cargo through receptor proteins like p62 as well as LC3. After closure, a double-membrane autophagosome is formed that next can fuse with lysosomes to form autophagolysosomes: this fusion provides the acidic environment and hydrolases to degrade engulfed cellular material. In (LO)AD, Tau gets hyperphosphorylated, which promotes its aggregation into fibrils that are targeted by the cell for autophagic breakdown. The pathway requires Tau to be ubiquitinated by the CHIP (carboxyl terminus of the Hsc70-interacting protein)-Hsc70 complex. Under normal circumstances autophagy can keep pace with the breakdown of Tau aggregates. When this process gets impaired, as occurs in the AD pathology, Tau aggregates cannot be cleared and start to build up, resulting in the formation of neurofibrillary tangles in the end. PICALM dysregulation in LOAD could affect its normal functioning; the interaction and endocytosis of SNARE proteins by PICALM, e.g. VAMP2, VAMP3 and VAMP8, regulates the autophagy process and, hence, removal of Tau. Moreover, through PICALM’s interaction with the complex adaptor protein 2 (AP2), it cross-links LC3 to the APP C-terminal fragment that makes the fragment to be taken up and broken down in the autolysosome
Fig. 4 Role of PICALM in autophagy and the degradation of tau fibrils. The catabolic autophagy cascade engulfs cytoplasmic content such as dysfunctional organelles, aggregated proteins or peptides for degradation in lysosomes. Autophagy can be initiated through different upstream (metabolic) signals that converge into the activation of two protein complexes, the ULK complex (ATG13, ATG101, FIP200 and ULK1) and the VPS34 complex (Atg6, Atg14, VPS15 and VPS34). One of the first steps is the formation of the phagophore that recruits ubiquitinated cargo through receptor proteins like p62 as well as LC3. After closure, a double-membrane autophagosome is formed that next can fuse with lysosomes to form autophagolysosomes: this fusion provides the acidic environment and hydrolases to degrade engulfed cellular material. In (LO)AD, Tau gets hyperphosphorylated, which promotes its aggregation into fibrils that are targeted by the cell for autophagic breakdown. The pathway requires Tau to be ubiquitinated by the CHIP (carboxyl terminus of the Hsc70-interacting protein)-Hsc70 complex. Under normal circumstances autophagy can keep pace with the breakdown of Tau aggregates. When this process gets impaired, as occurs in the AD pathology, Tau aggregates cannot be cleared and start to build up, resulting in the formation of neurofibrillary tangles in the end. PICALM dysregulation in LOAD could affect its normal functioning; the interaction and endocytosis of SNARE proteins by PICALM, e.g. VAMP2, VAMP3 and VAMP8, regulates the autophagy process and, hence, removal of Tau. Moreover, through PICALM’s interaction with the complex adaptor protein 2 (AP2), it cross-links LC3 to the APP C-terminal fragment that makes the fragment to be taken up and broken down in the autolysosomeCC BY · PubMed Central
Fig. 5 Involvement of LOAD risk factors at the BBB. Transport of Aβ through endothelial transcytosis is PICALM-dependent and a major pathway for clearing Aβ from the brain. Aβ-bound ApoE and free Aβ bind the low density lipoprotein receptor-related protein 1 (LRP1) that associates with PICALM during transcytosis. CD2AP contributes in the upkeep of BBB integrity through a process hypothesized to involve its binding-partner Rac1. Endothelial CD2AP further interacts with VCAM (CD106) and ICAM-1 (CD54), affecting immune cell extravasation
Fig. 5 Involvement of LOAD risk factors at the BBB. Transport of Aβ through endothelial transcytosis is PICALM-dependent and a major pathway for clearing Aβ from the brain. Aβ-bound ApoE and free Aβ bind the low density lipoprotein receptor-related protein 1 (LRP1) that associates with PICALM during transcytosis. CD2AP contributes in the upkeep of BBB integrity through a process hypothesized to involve its binding-partner Rac1. Endothelial CD2AP further interacts with VCAM (CD106) and ICAM-1 (CD54), affecting immune cell extravasationCC BY · PubMed Central
Fig. 6 Vesicular acidification by NHE6 impacts ApoE4 stability. The APOE receptor 2 (APOER2) binds the different ApoE isoforms, which are subsequently internalized into endosomes. Passing through the cellular transport axis, endosomes start to acidify through a continuous electrogenic proton influx, pumped into to lumen by V-ATPases. To ascertain that proton accretion is bound within limits, channels can exchange these protons for 2 Cl− or Na+, performed by i.a. the Na+/H+ exchanger NHE6. Under healthy conditions, the acidification enables the APOER2 to be dislodged from APOE, which then relocates to the cell surface again to contribute in N-methyl-D-aspartate receptor (NMDAR) activation. Fluctuations of pH are not only important for a proper receptor recycling, but also for a correct folding of ApoE. The isoelectric point of ApoE4 is higher as the ones of ApoE2 and E3, making its isoelectric point to be already reached in endosomes in contrast to the other variants. Hence, ApoE4 will adapt a molten globule state in sorting endosomes-lysosomes, which not only promotes APOER2 clustering (hindering recycling to the plasma membrane) but also displays a high affinity for phospholipids. These are most likely oxidatively damaged, impacting the mechanical characteristics of the membrane and, as such, their capacity to withstand disruptions e.g. induced by Aβ. The therapeutic potential of targeting this pH-linked instability of ApoE4 has been positively assessed, reducing the levels of the Na+/H+ exchanger NHE6 and using sodium channel blocking amiloride analogs. Aside from ApoE isoforms, the APOER2 interacts with the extracellular matrix serine protease – Reelin – in a competitive fashion. Upon activation by Reelin, a signaling cascade is induced which abrogates tau hyperphosphorylation and promotes the influx of Ca2+ through the NMDAR
Fig. 6 Vesicular acidification by NHE6 impacts ApoE4 stability. The APOE receptor 2 (APOER2) binds the different ApoE isoforms, which are subsequently internalized into endosomes. Passing through the cellular transport axis, endosomes start to acidify through a continuous electrogenic proton influx, pumped into to lumen by V-ATPases. To ascertain that proton accretion is bound within limits, channels can exchange these protons for 2 Cl− or Na+, performed by i.a. the Na+/H+ exchanger NHE6. Under healthy conditions, the acidification enables the APOER2 to be dislodged from APOE, which then relocates to the cell surface again to contribute in N-methyl-D-aspartate receptor (NMDAR) activation. Fluctuations of pH are not only important for a proper receptor recycling, but also for a correct folding of ApoE. The isoelectric point of ApoE4 is higher as the ones of ApoE2 and E3, making its isoelectric point to be already reached in endosomes in contrast to the other variants. Hence, ApoE4 will adapt a molten globule state in sorting endosomes-lysosomes, which not only promotes APOER2 clustering (hindering recycling to the plasma membrane) but also displays a high affinity for phospholipids. These are most likely oxidatively damaged, impacting the mechanical characteristics of the membrane and, as such, their capacity to withstand disruptions e.g. induced by Aβ. The therapeutic potential of targeting this pH-linked instability of ApoE4 has been positively assessed, reducing the levels of the Na+/H+ exchanger NHE6 and using sodium channel blocking amiloride analogs. Aside from ApoE isoforms, the APOER2 interacts with the extracellular matrix serine protease – Reelin – in a competitive fashion. Upon activation by Reelin, a signaling cascade is induced which abrogates tau hyperphosphorylation and promotes the influx of Ca2+ through the NMDARCC BY · PubMed Central

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Authors
Van Acker, Z. P., Bretou, M., & Annaert, W.
Affiliations
VIB-KU Leuven Center for Brain & Disease Research (BE)
Corresponding author
Annaert, Wim
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2019-06-03
Volume
14
Issue
1
Pages
20-20
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-019-0323-7
PMC
PMC6547588
OpenAlex
W2948656839
Cited by
222
References
171
Citations by year
2026: 10 · 2025: 31 · 2024: 53 · 2023: 26 · 2022: 26 · 2021: 40 · 2020: 31 · 2019: 5
FWCI
3.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Onderzoeksraad, KU Leuven (C16/15/073)
  • FWO (S006617N, G078117N, G05601N)
  • Hercules (AKUL/11/30, AKUL/13/39)
  • SAO (2917/033, S#20180020)
  • Alzheimer Association (AARF-18-564825)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
late-onset Alzheimer's disease, endolysosomal dysfunction, autophagy, autophagic flux, lysosomal homeostasis, genetic risk factors, APOE ε4, BIN1, CD2AP, PICALM, PLD3, TREM2, amyloid-beta clearance, blood-brain barrier, cholesterol metabolism, endocytic transport, aging, neurodegeneration
MeSH terms
Alzheimer Disease, Animals, Autophagy, Humans, Lysosomes, Membrane Glycoproteins, Risk Factors, Amyloid beta-Protein Precursor

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