Restoring microglial and astroglial homeostasis using DNA immunization in a Down Syndrome mouse model

Abstract

Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation as early as the age of 40. In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aβ1–11 fragment, in ameliorating Aβ-related neuropathology and rescue of cognitive and behavioral abilities. Anti-Aβ1–11 vaccination induced antibody production and facilitated clearance of soluble oligomers and small extracellular inclusions of Aβ from the hippocampus and cortex of Ts65Dn mice. This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglial and astroglial cells. Vaccinated Ts65Dn mice performed better in spatial-learning tasks, exhibited reduced motor hyperactivity typical for this strain, and restored short-term memory abilities. Our findings support the hypothesis that DS individuals may benefit from active immunotherapy against Aβ from a young age by slowing the progression of dementia.

Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis

“…This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglia and astrocytes (Illouz et al, 2019). These findings support the notion that immunotherapy against Aβ can slow the progression of dementia in DS, and that an anti-murine Aβ vaccination is safe to use in mice, as vaccinated wild-type (WT) mice exhibited no cognitive or other behavioral abnormalities that could indicate neurotoxicity (Illouz et al, 2019).…”

“…The AβCoreS construct was previously shown to delay cognitive decline and reduce human Aβ pathology in the 3xtgAD mouse model of AD (Olkhanud et al, 2012). A modified vaccine targeting murine Aβ, which is triplicated in the Ts65Dn mouse model of DS (Gupta, Dhanasekaran, & Gardiner, 2016), was also shown to induce anti-Aβ Ab production that facilitates clearance of soluble oligomers and small extracellular inclusions of Aβ from the hippocampus and cortex of Ts65Dn mice (Illouz, Madar, Biragyn, & Okun, 2019). This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglia and astrocytes (Illouz et al, 2019).…”

“…A modified vaccine targeting murine Aβ, which is triplicated in the Ts65Dn mouse model of DS (Gupta, Dhanasekaran, & Gardiner, 2016), was also shown to induce anti-Aβ Ab production that facilitates clearance of soluble oligomers and small extracellular inclusions of Aβ from the hippocampus and cortex of Ts65Dn mice (Illouz, Madar, Biragyn, & Okun, 2019). This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglia and astrocytes (Illouz et al, 2019). These findings support the notion that immunotherapy against Aβ can slow the progression of dementia in DS, and that an anti-murine Aβ vaccination is safe to use in mice, as vaccinated wild-type (WT) mice exhibited no cognitive or other behavioral abnormalities that could indicate neurotoxicity (Illouz et al, 2019).…”

“…Mouse models of trisomy-21 successfully recapitulate several aspects of DS, such as cholinergic neurodegeneration, elevated levels of Aβ and phospho-tau, and impaired cognitive ability (Rueda, Florez, & Martinez-Cue, 2012). However, these current DS models critically fail to recapitulate extra-cellular Aβ plaque accumulation (Illouz et al, 2019; Wiseman et al, 2018). Indeed, several DS models, including the Ts65Dn strain, overexpress murine Aβ, which does not aggregate as human Aβ, potentially due to three amino-acids differences in the N-terminus.…”

“…Humanized models of DS such as the Tc1 strain also lack plaque pathology due to a nonfunctional human APP gene (Gribble et al, 2013). Accordingly, these models lack plaque-associated microglial pathology (Illouz et al, 2019; Keren-Shaul et al, 2017; Krasemann et al, 2017). These considerations led us to use the 5xFAD strain that encompasses five mutations associated with Aβ pathology in EOAD (Oakley et al, 2006).…”