Antibody-Based In Vivo PET Imaging Detects Amyloid-β Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition

Meier, Silvio R.; Syvänen, Stina; Hultqvist, Greta; Fang, Xiaotian T.; Roshanbin, Sahar; Lannfelt, Lars; Neumann, Ulf; Sehlin, Dag

doi:10.2967/jnumed.118.213140

Cited by 39 publications

(37 citation statements)

References 29 publications

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“…The highest retention was observed in areas of abundant Aβ deposition, especially cortex, hippocampus, and thalamus, and also to some extent in the cerebellum, where pathology starts to emerge at this age. 23,30 This pattern resembles what we have previously reported for brain penetrating Aβ antibodies 30 and represents successful transcytosis of [ 125 I]Bapi-TXB2 across the BBB of brain capillaries. This was confirmed by nuclear track emulsion autoradiography in combination with immunostaining of Aβ and the vascular marker CD31, demonstrating that [ 125 I] Bapi-TXB2 crossed the BBB to interact with parenchymal Aβ pathology, while [ 125 I]Bapi did not, and that hot spots of Bapi were found around vessels with adjacent Aβ pathology.…”

Section: Discussionsupporting

confidence: 85%

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Sehlin

Stocki²,

Gustavsson

et al. 2020

FASEB j.

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Transferrin receptor 1 (TfR1) mediated transcytosis is an attractive strategy to enhance brain uptake of protein drugs, but translation remains a challenge. Here, a single domain shark antibody VNAR fragment (TXB2) with similar affinity to murine and human TfR1 was used to shuttle protein cargo into the brain. TXB2 was fused to a human IgG1 Fc domain (hFc) or to the amyloid‐β (Aβ) antibody bapineuzumab (Bapi). TXB2‐hFc displayed 20‐fold higher brain concentrations compared with a control VNAR‐hFc at 18 hours post‐injection in wt mice. At the same time point, brain concentrations of Bapi‐TXB2 was threefold higher than Bapi. In transgenic mice overexpressing human Aβ, the brain‐to‐blood concentration ratio increased with time due to interaction with intracerebral Aβ deposits. The relatively stable threefold difference between Bapi‐TXB2 and Bapi was observed for up to 6 days after injection. PET imaging and ex vivo autoradiography revealed more parenchymal distribution of Bapi‐TXB2 compared with Bapi. In conclusion, the TXB2 VNAR shuttle markedly increased brain uptake of protein cargo and increased brain concentrations of the Aβ binding antibody Bapi.

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Section: Discussionsupporting

confidence: 85%

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Sehlin

Stocki²,

Gustavsson

et al. 2020

FASEB j.

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“…In contrast, we found a highly stable background signal in WT mice in treatment and vehicle groups using the amyloid ligand [ 18 F]-florbetaben, which encourages the use of the mouse model in combination with the earlier-validated quantification method 16 . A recent PET study showed the ability to detect non-fibrillar Aβ forms in vivo during treatment of transgenic ArcSwe mice with another BACE1 inhibitor 23 , whereas our PET ligand binds only fibrillary parts of the plaque. Future monitoring regimes could therefore entail dual PET with selective tracers to capture both components of amyloidosis during BACE1 inhibition.…”

Section: Discussionmentioning

confidence: 95%

Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation

Brendel¹,

Jaworska²,

Overhoff³

et al. 2018

Theranostics

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Beta secretase (BACE) inhibitors are promising therapeutic compounds currently in clinical phase II/III trials. Preclinical [18F]-florbetaben (FBB) amyloid PET imaging facilitates longitudinal monitoring of amyloidosis in Alzheimer's disease (AD) mouse models. Therefore, we applied this theranostic concept to investigate, by serial FBB PET, the efficacy of a novel BACE1 inhibitor in the PS2APP mouse, which is characterized by early and massive amyloid deposition.Methods: PS2APP and C57BL/6 (WT) mice were assigned to treatment (PS2APP: N=13; WT: N=11) and vehicle control (PS2APP: N=13; WT: N=11) groups at the age of 9.5 months. All animals had a baseline PET scan and follow-up scans at two months and after completion of the four-month treatment period. In addition to this longitudinal analysis of cerebral amyloidosis by PET, we undertook biochemical amyloid peptide quantification and histological amyloid plaque analyses after the final PET session.Results: BACE1 inhibitor-treated transgenic mice revealed a progression of the frontal cortical amyloid signal by 8.4 ± 2.2% during the whole treatment period, which was distinctly lower when compared to vehicle-treated mice (15.3 ± 4.4%, p<0.001). A full inhibition of progression was evident in regions with <3.7% of the increase in controls, whereas regions with >10% of the increase in controls showed only 40% attenuation with BACE1 inhibition. BACE1 inhibition in mice with lower amyloidosis at treatment initiation showed a higher efficacy in attenuating progression to PET. A predominant reduction of small plaques in treated mice indicated a main effect of BACE1 on inhibition of de novo amyloidogenesis.Conclusions: This theranostic study with BACE1 treatment in a transgenic AD model together with amyloid PET monitoring indicated that progression of amyloidosis is more effectively reduced in regions with low initial plaque development and revealed the need of an early treatment initiation during amyloidogenesis.

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“…Thus, data demonstrate a potential role of BACE1 in vessel-localized Aβ production and vascular Aβ deposition. The BACE1 inhibitor NB-360 attenuates Aβ in preclinical AD models [115,116], and was recently investigated in the APPDutch CAA mouse model [117]. APPDutch mice develop leptomeningeal and cortical CAA composed primarily of Aβ40, without exhibiting parenchymal plaques.…”

Section: Limited Efficacy Of Aβ-targeted Therapeutics On Vascular Amymentioning

confidence: 99%

Potential Role of Venular Amyloid in Alzheimer’s Disease Pathogenesis

Morrone

Bishay

McLaurin

2020

IJMS

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Insurmountable evidence has demonstrated a strong association between Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (Aβ) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial Aβ, while the accumulation of Aβ in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase Aβ deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular Aβ deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop Aβ-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.

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Antibody-Based In Vivo PET Imaging Detects Amyloid-β Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition

Cited by 39 publications

References 29 publications

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation

Potential Role of Venular Amyloid in Alzheimer’s Disease Pathogenesis

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