Amyloid beta immunization worsens iron deposits in the choroid plexus and cerebral microbleeds

Abstract

Anti-Aβ immunotherapy provides potential benefits in Alzheimer’s disease patients. Nevertheless, strategies based on Aβ1-42 peptide induced encephalomyelitis and possible microhemorrhages. These outcomes were not expected from studies performed in rodents. It is critical to determine if other animal models better predict side effects of immunotherapies. Mouse lemur primates can develop amyloidosis with aging. Here we used old lemurs to study immunotherapy based on Aβ1-42 or Aβ-derivative (K6Aβ1-30). We followed anti-Aβ40 IgG and IgM responses as well as Aβ levels in plasma. In-vivo magnetic resonance imaging and histology were used to evaluate amyloidosis, neuroinflammation, vasogenic edema, microhemorrhages, and brain iron deposits. The animals responded mainly to the Aβ1-42 immunogen. This treatment induced immune response and increased Aβ levels in plasma but also microhemorrhages and iron deposits in the choroid plexus. A complementary study of untreated lemurs showed iron accumulation in the choroid plexus with normal aging. Worsening of iron accumulation is thus a potential side effect of Aβ-immunization at prodromal stages of Alzheimer’s disease, and should be monitored in clinical trials.

The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer's disease: Two sides of the same coin

“…Therapies aimed at reducing amyloid have proved problematic in clinical trials as the removal of amyloid from the brain releases free iron and destabilizes microvessels 232 . Targeted reduction of Aβ deposition and amyloidogenesis with secretase inhibitors and immunotherapies leads to iron accumulation and cognitive deficits.…”

Age-associated evolution of plasmatic amyloid in mouse lemur primates: relationship with intracellular amyloid deposition

“…Here, we evaluated plasmatic Aβ in mouse lemur primates, a model of cerebral aging that can spontaneously develop intracellular (Joseph-Mathurin et al, 2013; Mestre-Frances et al, 2000) and extracellular (Bons et al, 1991) Aβ deposits while aging. In mouse lemurs, plasma Aβ is already used as a biomarker in drug studies (Trouche et al, 2009; Joseph-Mathurin et al, 2013) although the age effect on plasmatic Aβ has never been studied. In mouse lemurs, plasma Aβ concentrations are much lower than in transgenic mice, as mouse lemurs are non transgenic animals who are not overexpressing Aβ.…”

“…Studies of therapeutic interventions in primates also revealed changes in plasmatic Aβ. For example, increased plasmatic Aβ is detected following active immunotherapy in primates such as the mouse lemur (Trouche et al, 2009; Joseph-Mathurin et al, 2013) and the caribbean vervet (Lemere et al, 2004). …”

“…This small primate (70–150g) has a short lifespan of approximately 12 years. A subcategory of aged lemurs can develop both extracellular (Bons et al, 1991) and intracellular (Joseph-Mathurin et al, 2013; Mestre-Frances et al, 2000) Aβ deposits and Tau pathologies (Kraska et al, 2011). Our results suggest increased plasmatic Aβ levels in a subpopulation of aged lemurs.…”

Imagerie cérébrale : outils, principes et utilisations de la clinique aux sciences cognitives comparatives

“…Dans de nombreux cas, les images reposent sur le contraste spontané des tissus et de nombreux paramètres biologiques sont étudiés avec cette méthode. Par exemple, les images acquises en IRM permettent d'étudier l'anatomie macroscopique (figure A-B) ou microscopique (figure 2C-D) (Petiet et al 2012), l'accumulation de fer ou de microhémorragies dans le cerveau (Joseph-Mathurin et al 2013), le système vasculaire (angiographie par résonance magnétique) (figure 2E) (El Tannir El Tayara et al 2010), la perfusion (Faure et al 2011), la diffusion des molécules d'eau (Le Bihan et al 1986) ou l'activation du cerveau (IRM fonctionnelle) (Kwong et al 1992). Dans ce dernier cas, on peut visualiser, avec une résolution spatiale et temporelle exceptionnelles, les régions du cerveau activées par une tâche cognitive ou comportementale.…”