A\u03b243 in human Alzheimer\u2019s disease: effects of active A\u03b242 immunization

Lieke Jäkel,Delphine Boche,Marcel M Verbeek,James A R Nicoll

doi:10.1186/s40478-019-0791-6

Abstract

Neuropathological follow-up of patients with Alzheimer’s disease (AD) who participated in the first clinical trial of Amyloid-β 42 (Aβ42) immunization (AN1792, Elan Pharmaceuticals) has shown that immunization can induce removal of Aβ42 and Aβ40 from plaques, whereas analysis of the cerebral vessels has shown increased levels of these Aβ peptides in cerebral amyloid angiopathy (CAA). Aβ43 has been less frequently studied in AD, but its aggregation propensity and neurotoxic properties suggest it may have an important pathogenic role. In the current study we show by using immunohistochemistry that in unimmunized AD patients Aβ43 is a frequent constituent of plaques (6.0% immunostained area), similar to Aβ42 (3.9% immunostained area). Aβ43 immunostained area was significantly higher than that of Aβ40 (2.3%, p = 0.006). In addition, we show that Aβ43 is only a minor component of CAA in both parenchymal vessels (1.5 Aβ43-positive vessels per cm2 cortex vs. 5.3 Aβ42-positive vessels, p = 0.03, and 6.2 Aβ40-positive vessels, p = 0.045) and leptomeningeal vessels (5.6% Aβ43-positive vessels vs. 17.3% Aβ42-positive vessels, p = 0.007, and 27.4% Aβ40-positive vessels, p = 0.003). Furthermore, we have shown that Aβ43 is cleared from plaques after Aβ immunotherapy, similar to Aβ42 and Aβ40. Cerebrovascular Aβ43 levels did not change after immunotherapy.

Highlights

Alzheimer’s disease (AD) is characterized by the extracellular accumulation of the Amyloid-β (Aβ) protein in the brain parenchyma as plaques and in cerebrovascular blood vessel walls as cerebral amyloid angiopathy (CAA), and the intraneuronal accumulation of the tau protein
The resulting Aβ49 or Aβ48 are sequentially cleaved in increments of three amino acids, which leads to the production pathways Aβ49 → Aβ46 → Aβ43 → Aβ40 and Aβ48 → Aβ45 → Amyloid-β 42 (Aβ42) [7, 26, 32]
Aβ peptides in plaques in AD cases Qualitative assessment of reactivity of the different Aβ antibodies in the middle temporal lobe showed that anti-Aβ43 and anti-Aβ42 antibodies immunolabeled diffuse and dense-core plaques, whereas Aβ40 detection was largely confined to plaque cores (Fig. 2a-f)

Summary

Introduction

Alzheimer’s disease (AD) is characterized by the extracellular accumulation of the Amyloid-β (Aβ) protein in the brain parenchyma as plaques and in cerebrovascular blood vessel walls as cerebral amyloid angiopathy (CAA), and the intraneuronal accumulation of the tau protein. It is hypothesized that CAA is caused by dysfunctional Aβ elimination: a process that may include enzymatic degradation, receptor-mediated clearance across the blood-brain barrier (BBB), and drainage with interstitial fluid along perivascular pathways [33]. Blockage of these pathways may lead to aggregation of Aβ in the vessel walls as CAA [10, 22]. Aβ42 is a major constituent of plaques, whereas some studies show that Aβ40 is the predominant species in CAA [9, 28].

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