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Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E

Robert, Jerome, Button, Emily B., Martin, Emma M., McAlary, Luke, Gidden, Zoe, Gilmour, Megan, Boyce, Guilaine, Caffrey, Tara M., Agbay, Andrew, Clark, Amanda, Silverman, Judith M., Cashman, Neil R., Wellington, Cheryl L.·2020·Molecular Neurodegeneration
DOI 10.1186/s13024-020-00366-8PMC PMC7093966
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Abstract

Background: Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood. Methods: Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding. Results: We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE. Conclusion: The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.

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Figures

Fig. 1 Human in vitro bioengineered vessels model CAA. a Immunofluorescent staining for CD31 confirms the formation of an endothelial monolayer surrounded by several layers of SMC stained for α-SM actin. b Evans blue staining confirms a tight endothelial barrier 10 days after endothelialisation. In (a) and (b), autofluorescence of the scaffold material is visible in the DAPI channel. c After injecting 1 μM of Aβ42 in the antelumen (tissue chamber), tissue chamber and circulation media were collected and Aβ42 was quantified by ELISA. d-e 24 h after injection of the indicated Aβ42 concentration into the tissue chamber, tissues were lysed in RIPA buffer before solubilizing the pellet in GuHCl followed by Aβ42 quantification using ELISA. f After injecting 1 μM of Aβ42 in the tissue chamber, 200 μg/mL of HDL was circulated through the lumen. After 24 h, Aβ42 accumulation was measured as above. g A blocking antibody against the HDL binding protein SR-BI was circulated in the presence of 200 μg/mL of HDL or BSA through the lumen after injecting Aβ42 into the tissue chamber. Aβ42 accumulation was measured as above. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’ t-test or one way ANOVA *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001
Fig. 1 Human in vitro bioengineered vessels model CAA. a Immunofluorescent staining for CD31 confirms the formation of an endothelial monolayer surrounded by several layers of SMC stained for α-SM actin. b Evans blue staining confirms a tight endothelial barrier 10 days after endothelialisation. In (a) and (b), autofluorescence of the scaffold material is visible in the DAPI channel. c After injecting 1 μM of Aβ42 in the antelumen (tissue chamber), tissue chamber and circulation media were collected and Aβ42 was quantified by ELISA. d-e 24 h after injection of the indicated Aβ42 concentration into the tissue chamber, tissues were lysed in RIPA buffer before solubilizing the pellet in GuHCl followed by Aβ42 quantification using ELISA. f After injecting 1 μM of Aβ42 in the tissue chamber, 200 μg/mL of HDL was circulated through the lumen. After 24 h, Aβ42 accumulation was measured as above. g A blocking antibody against the HDL binding protein SR-BI was circulated in the presence of 200 μg/mL of HDL or BSA through the lumen after injecting Aβ42 into the tissue chamber. Aβ42 accumulation was measured as above. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’ t-test or one way ANOVA *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001CC BY · PubMed Central
Fig. 2 HDL, but not LDL, reduces Aβ42 accumulation in the bioengineered vessels by penetrating in the vascular wall. a Aβ42 monomers (1 μM) were injected into the tissue chamber concomitantly with circulating 200 μg/mL (total protein) of HDL or mixLDL (LDL, VLDL and ILDL) through the lumen. After 24 h, tissues were lysed in RIPA and Aβ42 was measured using ELISA. After injection of Aβ42 as above, HDL (200 μg/mL) was circulated through the lumen and Aβ42 accumulation was measured after 6 h (b) or 72 h (c). d Schematic representation of the experimental design for panels (e) and (f). Bioengineered vessels were treated with Aβ42 with or without HDL (1) or pre-treated with 200 μg/mL HDL for 24 h before injecting Aβ42 without (2) or with (3) washing. 24 h after Aβ42 injection, Aβ accumulation was measured in RIPA (e) or GuHCl (f) fractions. g HDL (200 μg/mL) was circulated through lumen of bioengineered vessels for 24 h before measuring apoA-I in vascular tissues using ELISA. h Alexa 633-labeled HDL (depicted in white) was circulated through the circulation of engineered vessel before, washing, fixing and imaging using confocal microscopy, representative image of three bioengineered vessels. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test or one way ANOVA *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001
Fig. 2 HDL, but not LDL, reduces Aβ42 accumulation in the bioengineered vessels by penetrating in the vascular wall. a Aβ42 monomers (1 μM) were injected into the tissue chamber concomitantly with circulating 200 μg/mL (total protein) of HDL or mixLDL (LDL, VLDL and ILDL) through the lumen. After 24 h, tissues were lysed in RIPA and Aβ42 was measured using ELISA. After injection of Aβ42 as above, HDL (200 μg/mL) was circulated through the lumen and Aβ42 accumulation was measured after 6 h (b) or 72 h (c). d Schematic representation of the experimental design for panels (e) and (f). Bioengineered vessels were treated with Aβ42 with or without HDL (1) or pre-treated with 200 μg/mL HDL for 24 h before injecting Aβ42 without (2) or with (3) washing. 24 h after Aβ42 injection, Aβ accumulation was measured in RIPA (e) or GuHCl (f) fractions. g HDL (200 μg/mL) was circulated through lumen of bioengineered vessels for 24 h before measuring apoA-I in vascular tissues using ELISA. h Alexa 633-labeled HDL (depicted in white) was circulated through the circulation of engineered vessel before, washing, fixing and imaging using confocal microscopy, representative image of three bioengineered vessels. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test or one way ANOVA *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001CC BY · PubMed Central
Fig. 3 HDL reduces Aβ42 uptake and LRP1 levels in SMC and blocking LRP1 with RAP reduces Aβ42 accumulation in bioengineered vessels. SMC were grown as 2D monolayers for 2 d before treating with 1 μM FITC-Aβ42 without or with 200 μg/mL of HDL for 3 h (a) or 24 h (b) before dissociating the cells and counting using flow cytometry. c SMC were grown in 2D culture for 3 d before treating with FITC-Aβ42 (5 μM, yellow) with 200 μg/mL of HDL or BSA for 24 h and imaged using microscopy. d SMC were grown for 3 days in 2D culture were treated with the indicated HDL concentration. LRP1 protein levels were measured by Western blot and normalized to GAPDH. e Aβ42 monomers (1 μM) were injected into the tissue chamber concomitantly with circulating 200 μg/mL of HDL or BSA through the lumen. After 24 h, tissues were lysed in RIPA. LRP1 protein levels were measured in bioengineered vessels using Western blot and normalized to GAPDH. f Bioengineered vessels were treated with 1 μM Aβ42 with or without recombinant RAP in the circulation media to block LRP1. After 24 h, tissues were lysed in RIPA and Aβ42 accumulation was measured by ELISA. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test or one way ANOVA *P < 0.05
Fig. 3 HDL reduces Aβ42 uptake and LRP1 levels in SMC and blocking LRP1 with RAP reduces Aβ42 accumulation in bioengineered vessels. SMC were grown as 2D monolayers for 2 d before treating with 1 μM FITC-Aβ42 without or with 200 μg/mL of HDL for 3 h (a) or 24 h (b) before dissociating the cells and counting using flow cytometry. c SMC were grown in 2D culture for 3 d before treating with FITC-Aβ42 (5 μM, yellow) with 200 μg/mL of HDL or BSA for 24 h and imaged using microscopy. d SMC were grown for 3 days in 2D culture were treated with the indicated HDL concentration. LRP1 protein levels were measured by Western blot and normalized to GAPDH. e Aβ42 monomers (1 μM) were injected into the tissue chamber concomitantly with circulating 200 μg/mL of HDL or BSA through the lumen. After 24 h, tissues were lysed in RIPA. LRP1 protein levels were measured in bioengineered vessels using Western blot and normalized to GAPDH. f Bioengineered vessels were treated with 1 μM Aβ42 with or without recombinant RAP in the circulation media to block LRP1. After 24 h, tissues were lysed in RIPA and Aβ42 accumulation was measured by ELISA. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test or one way ANOVA *P < 0.05CC BY · PubMed Central
Fig. 4 Aβ42 binds to collagen-I in the vascular wall of post-mortem human brain and in bioengineered vessels and HDL reduces collagen-I level in SMC. a SMC were grown for 1 d in chamber slides before treating with 0.5 μM FITC-Aβ42 (yellow) and 200 μg/ml HDL. After 24 h, cells were fixed and cell membranes were stained using wheat germ agglutinin (WGA, magenta) and an antibody against collagen-I (cyan) was used to stain the ECM. Yellow arrows show intracellular Aβ42 and magenta arrows show collagen-I/Aβ42 co-localization. b Human cortex (Brodmann area 9) from four donors was stained for Aβ using 6E10 (yellow) and collagen-I (magenta) and expanded views of vascular (1) and cortical (2) Aβ fibrillar plaques are presented on the right. c Bioengineered vessels treated with Aβ42 monomers for 24 h were stained for collagen-I (yellow) and Aβ (6E10, magenta). White arrows show co-localization of collagen-I and Aβ42. d SMC were grown on 2D coverslips for 24 h before incubating with 0.5 μM FITC-Aβ42 (yellow) and 200 μg/mL HDL. SMC were then fixed and stained for collagen-I (magenta). Details of collagen-I fibres and Aβ42 co-localization are presented on the right. e SMC were grown for 24 h in 2D culture before treating with 1 μM Aβ42 with or without 200 μg/mL HDL. After 24 h, cells were lysed, collagen-I expression was measured by Western blot and normalized to actin levels. f Bioengineered vessels were treated with 1 μM Aβ42 and 200 μg/mL HDL as above. After 24 h, bioengineered vessels were lysed in RIPA and collagen-I levels were measured by Western blot and normalized to actin levels. All images are representative of at least 3 individual experiments or 4 donors and were imaged using confocal microscopy. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test *P < 0.05
Fig. 4 Aβ42 binds to collagen-I in the vascular wall of post-mortem human brain and in bioengineered vessels and HDL reduces collagen-I level in SMC. a SMC were grown for 1 d in chamber slides before treating with 0.5 μM FITC-Aβ42 (yellow) and 200 μg/ml HDL. After 24 h, cells were fixed and cell membranes were stained using wheat germ agglutinin (WGA, magenta) and an antibody against collagen-I (cyan) was used to stain the ECM. Yellow arrows show intracellular Aβ42 and magenta arrows show collagen-I/Aβ42 co-localization. b Human cortex (Brodmann area 9) from four donors was stained for Aβ using 6E10 (yellow) and collagen-I (magenta) and expanded views of vascular (1) and cortical (2) Aβ fibrillar plaques are presented on the right. c Bioengineered vessels treated with Aβ42 monomers for 24 h were stained for collagen-I (yellow) and Aβ (6E10, magenta). White arrows show co-localization of collagen-I and Aβ42. d SMC were grown on 2D coverslips for 24 h before incubating with 0.5 μM FITC-Aβ42 (yellow) and 200 μg/mL HDL. SMC were then fixed and stained for collagen-I (magenta). Details of collagen-I fibres and Aβ42 co-localization are presented on the right. e SMC were grown for 24 h in 2D culture before treating with 1 μM Aβ42 with or without 200 μg/mL HDL. After 24 h, cells were lysed, collagen-I expression was measured by Western blot and normalized to actin levels. f Bioengineered vessels were treated with 1 μM Aβ42 and 200 μg/mL HDL as above. After 24 h, bioengineered vessels were lysed in RIPA and collagen-I levels were measured by Western blot and normalized to actin levels. All images are representative of at least 3 individual experiments or 4 donors and were imaged using confocal microscopy. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test *P < 0.05CC BY · PubMed Central
Fig. 5 HDL binds to both collagen-I and to Aβ42 to form a complex and increases Aβ transport through the bioengineered vessel wall primarily by HDL-apoE particles. a SMC were grown for 3 d on 2D coverslips before incubating with 0.5 μM FITC-Aβ42 (depicted as yellow) and 200 μg/ml Alexa-633 labeled HDL (depicted as cyan). After 24 h, cells were fixed and stained for collagen-I (magenta) before imaging by confocal microscopy. White arrows show co-localization of Aβ42, HDL and collagen-I. b Black 96 well-plates were coated either with 50 μg/mL rat-tail collagen-I or 10% BSA as protein control for 24 h before incubating with a solution of 1 μM of FITC-Aβ42 with or without 200 μg/mL of HDL. After 24 h and extensive PBS washes, fluorescence representing bound Aβ42 was measured at 520 nm, excitation 490 nm. c 1 μM Aβ42 were incubated either with 200 μg/mL of HDL or BSA for 24 h at 37 °C before gel-filtration chromatography separation. Fractions were dot blotted and immunodetected for Aβ (6E10) or HDL (apoA-II). The intensity of each fraction on the dot blot was quantified, normalized between 0 and 100% and graphed on the left panel. The right panel shows a representative dot blot used for quantification. d 1 μM Aβ42 was injected in the tissue chamber of bioengineered vessels and 200 μg/mL of HDL was circulated through the lumen. After 24 h, tissues were homogenized in TBS to collect soluble Aβ, which was quantified in the tissue (c) or circulating media (d) by ELISA. f 1 μM Aβ42 was injected in the tissue chamber of bioengineered vessels and 200 μg/mL of HDL was circulated through the lumen. After 24 h vessels were lysed in RIPA and protein distribution was analysed using non-denaturing native blot probed for collagen-I, apoE, apoA-II, apoA-I and Aβ (6E10). g HDL was enriched for or depleted of apoE using an apoE immunoaffinity column. Bioengineered vessels were then treated with either fraction (200 μg/mL) in the presence of 1 μM Aβ42 as above before measuring Aβ deposition in the RIPA-soluble fraction. h RIPA lysates from engineered vessels were then analysed using non-denaturing native blot probed for collagen-I and apoE. i Black 96-well plates were coated either with 50 μg/mL rat-tail collagen-I or 10% BSA for 24 h before incubating with a solution of 1 μM of FITC-Aβ42 with or without 200 μg/ml of total HDL, apoE-depleted HDL or apoE-enriched HDL. After 24 h and extensive PBS washes, fluorescence was measured at 520 nm, excitation 490 nm. FPLC data and Western blots are representative of at least 3 individual experiments. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test or one way ANOVA *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001
Fig. 5 HDL binds to both collagen-I and to Aβ42 to form a complex and increases Aβ transport through the bioengineered vessel wall primarily by HDL-apoE particles. a SMC were grown for 3 d on 2D coverslips before incubating with 0.5 μM FITC-Aβ42 (depicted as yellow) and 200 μg/ml Alexa-633 labeled HDL (depicted as cyan). After 24 h, cells were fixed and stained for collagen-I (magenta) before imaging by confocal microscopy. White arrows show co-localization of Aβ42, HDL and collagen-I. b Black 96 well-plates were coated either with 50 μg/mL rat-tail collagen-I or 10% BSA as protein control for 24 h before incubating with a solution of 1 μM of FITC-Aβ42 with or without 200 μg/mL of HDL. After 24 h and extensive PBS washes, fluorescence representing bound Aβ42 was measured at 520 nm, excitation 490 nm. c 1 μM Aβ42 were incubated either with 200 μg/mL of HDL or BSA for 24 h at 37 °C before gel-filtration chromatography separation. Fractions were dot blotted and immunodetected for Aβ (6E10) or HDL (apoA-II). The intensity of each fraction on the dot blot was quantified, normalized between 0 and 100% and graphed on the left panel. The right panel shows a representative dot blot used for quantification. d 1 μM Aβ42 was injected in the tissue chamber of bioengineered vessels and 200 μg/mL of HDL was circulated through the lumen. After 24 h, tissues were homogenized in TBS to collect soluble Aβ, which was quantified in the tissue (c) or circulating media (d) by ELISA. f 1 μM Aβ42 was injected in the tissue chamber of bioengineered vessels and 200 μg/mL of HDL was circulated through the lumen. After 24 h vessels were lysed in RIPA and protein distribution was analysed using non-denaturing native blot probed for collagen-I, apoE, apoA-II, apoA-I and Aβ (6E10). g HDL was enriched for or depleted of apoE using an apoE immunoaffinity column. Bioengineered vessels were then treated with either fraction (200 μg/mL) in the presence of 1 μM Aβ42 as above before measuring Aβ deposition in the RIPA-soluble fraction. h RIPA lysates from engineered vessels were then analysed using non-denaturing native blot probed for collagen-I and apoE. i Black 96-well plates were coated either with 50 μg/mL rat-tail collagen-I or 10% BSA for 24 h before incubating with a solution of 1 μM of FITC-Aβ42 with or without 200 μg/ml of total HDL, apoE-depleted HDL or apoE-enriched HDL. After 24 h and extensive PBS washes, fluorescence was measured at 520 nm, excitation 490 nm. FPLC data and Western blots are representative of at least 3 individual experiments. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test or one way ANOVA *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001CC BY · PubMed Central
Fig. 6 Bioengineered vessels with astrocytes have reduced Aβ42 accumulation compared to bioengineered vessel lacking astrocytes and astrocyte-derived apoE in tissue chamber media reduces Aβ42 binding to collagen-I. a Immunofluorescent staining confirms the formation of an endothelial monolayer (CD31) surrounded by several layers of SMC (α-SM actin) with astrocytes genotyped as APOEε3/3 on the antelumen (GFAP). b 1 μM Aβ42 was injected into the tissue chamber of bioengineered vessels without (bipartite) or with astrocytes (tripartite). After 24 h, tissues were lysed in RIPA and Aβ42 accumulation was quantified using ELISA. c apoE levels in bipartite or tripartite bioengineered vessels were measured in RIPA lysate by immunoblot and normalized to GAPDH. d Astrocyte-secreted apoE levels in the circulation and chamber media were measured by ELISA. e Black 96-well plates were coated either with 50 μg/mL rat-tail collagen-I or 10% BSA for 24 h before incubating with a solution of 1 μM of FITC-Aβ42 in conditioned media from the chamber or circulating media from bipartite or tripartite bioengineered vessels. After 24 h and extensive washes, fluorescence was measured at 520 nm, excitation 490 nm. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test or one way ANOVA *P < 0.05 and **P < 0.01. L: lumen
Fig. 6 Bioengineered vessels with astrocytes have reduced Aβ42 accumulation compared to bioengineered vessel lacking astrocytes and astrocyte-derived apoE in tissue chamber media reduces Aβ42 binding to collagen-I. a Immunofluorescent staining confirms the formation of an endothelial monolayer (CD31) surrounded by several layers of SMC (α-SM actin) with astrocytes genotyped as APOEε3/3 on the antelumen (GFAP). b 1 μM Aβ42 was injected into the tissue chamber of bioengineered vessels without (bipartite) or with astrocytes (tripartite). After 24 h, tissues were lysed in RIPA and Aβ42 accumulation was quantified using ELISA. c apoE levels in bipartite or tripartite bioengineered vessels were measured in RIPA lysate by immunoblot and normalized to GAPDH. d Astrocyte-secreted apoE levels in the circulation and chamber media were measured by ELISA. e Black 96-well plates were coated either with 50 μg/mL rat-tail collagen-I or 10% BSA for 24 h before incubating with a solution of 1 μM of FITC-Aβ42 in conditioned media from the chamber or circulating media from bipartite or tripartite bioengineered vessels. After 24 h and extensive washes, fluorescence was measured at 520 nm, excitation 490 nm. Points in graphed data represent individual bioengineered vessels, bars represent mean, error bars represent ±SEM and analysed by Student’s t-test or one way ANOVA *P < 0.05 and **P < 0.01. L: lumenCC BY · PubMed Central
Fig. 7 Schematic of the mechanisms by which HDL is hypothesized to protect cerebrovascular functions in AD. a In the absence of HDL, when Aβ peptides enter the vessel wall they are either taken up by SMC via LRP1 (1a) or become trapped in ECM, particularly when enriched in collagen-I (1b). 2) Accumulation of Aβ in the vessel wall induces endothelial activation and subsequent binding and transmigration of blood-derived circulating monocytes. 3) Astrocytes on the antelumen of penetrating arteries secret apoE that reduces collagen-I levels in the vascular wall. b in the presence of HDL, 4) HDL reduces monocyte binding via SR-BI (4a), whereas reduction of CAA is independent of SR-BI (4b). 5) HDL enters the cerebrovascular wall through undefined mechanisms and reduce Aβ uptake by SMC maybe by reducing LRP1 levels (5a), bind and remodel collagen-I fibres via HDL-apoE particles (5b) and form a complex with Aβ (5c), all of which increase luminal recovery of Aβ. 6) The reduction of CAA is specific to HDL
Fig. 7 Schematic of the mechanisms by which HDL is hypothesized to protect cerebrovascular functions in AD. a In the absence of HDL, when Aβ peptides enter the vessel wall they are either taken up by SMC via LRP1 (1a) or become trapped in ECM, particularly when enriched in collagen-I (1b). 2) Accumulation of Aβ in the vessel wall induces endothelial activation and subsequent binding and transmigration of blood-derived circulating monocytes. 3) Astrocytes on the antelumen of penetrating arteries secret apoE that reduces collagen-I levels in the vascular wall. b in the presence of HDL, 4) HDL reduces monocyte binding via SR-BI (4a), whereas reduction of CAA is independent of SR-BI (4b). 5) HDL enters the cerebrovascular wall through undefined mechanisms and reduce Aβ uptake by SMC maybe by reducing LRP1 levels (5a), bind and remodel collagen-I fibres via HDL-apoE particles (5b) and form a complex with Aβ (5c), all of which increase luminal recovery of Aβ. 6) The reduction of CAA is specific to HDLCC BY · PubMed Central

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Metadata

Authors
Robert, J., Button, E. B., Martin, E. M., McAlary, L., Gidden, Z., Gilmour, M., Boyce, G., Caffrey, T. M., Agbay, A., Clark, A., Silverman, J. M., Cashman, N. R., & Wellington, C. L.
ORCID
Robert, Jerome
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2020-03-25
Volume
15
Issue
1
ISSN
1750-1326
DOI
10.1186/s13024-020-00366-8
PMC
PMC7093966
Cited by
27
References
15
Language
en
Licence
Funders
  • Weston Brain Institute (RR182093, RR150048)
  • Natural Sciences and Engineering Research Council of Canada
  • Cure Alzheimer's Fund (.)

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