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

Abstract

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β peptide (Aβ) deposition in the brain is one of its hallmarks and the measure of plasma Aβ is considered to be a biomarker for anti-amyloid drug efficacy in animal models of AD. However, age-associated plasmatic Aβ modulation in animal models is practically never addressed in the literature. Mouse lemur primates are used as a model of normal and AD-like cerebral aging. Here, we studied the effect of age on plasmatic Aβ in 58 mouse lemurs aged from 1 to 10 years. A subset of animals presented high plasmatic Aβ and the proportion of animals with high plasmatic Aβ was higher in aged animals as compared to young ones. Histological evaluation of the brain of some of these animals was carried out to assess extracellular and intracellular amyloid load. In aged lemurs, plasmatic Aβ was negatively correlated with the density of neurons accumulating deposits of Aβ.

Association of plasma β-amyloid with MRI markers of structural brain aging the 3-City Dijon study

“…The precise mechanisms underlying these associations remain unclear but amyloid production and accumulation are likely to be responsible for synaptic and neuronal degeneration and gray matter atrophy (Hardy and Selkoe, 2002). Animal studies have shown plasma Ab to be negatively correlated with density of neurons accumulating Ab deposits (Roy et al, 2014) and that elevations in both brain and circulating Ab levels can induce cerebrovascular dysfunction, with distinct and additive effects (Park et al, 2013). Cerebrovascular damage (e.g., brain hypoperfusion, hypoxia) may lead to neurodegenerative changes, or accumulation and reduced clearance of Ab from the brain, further amplifying neuronal injury and neurodegeneration (Bell et al, 2010;Deane et al, 2004).…”

“…Recent animal studies examining the direct relation of plasma Ab to cerebral Ab deposits have reported a negative correlation of plasma Ab 1e40 with density of neurons accumulating Ab deposits (Roy et al, 2014). Similarly, in humans, higher plasma Ab 1e40 levels and lower plasma Ab 1e42 /Ab 1e40 ratio levels have been linked to increased Ab deposition in the brain (Devanand et al, 2011;Lui et al, 2010;Tzen et al, 2014).…”

Synaptic activity and Alzheimer's disease: a critical update

“…Intriguingly, in brain areas where plaques were reduced intraneuronal Aβ was increased, and presented an inverse correlation with levels of synaptophysin (Tampellini et al, 2010 ). Intraneuronal Aβ accumulation has been observed in human AD brains, in several rodent models of AD (Gouras et al, 2000 ; D'Andrea et al, 2001 ; Busciglio et al, 2002 ; Mori et al, 2002 ; Oddo et al, 2003 ; Cataldo et al, 2004 ; Echeverria et al, 2004 ; Cruz et al, 2006 ; Oakley et al, 2006 ; LaFerla et al, 2007 ), and, more recently, also in brains of aged mouse lemur primates (Roy et al, 2014 ). Within neurons, Aβ accumulates on the outer membrane of multivesicular bodies, both in somas and neurites (Takahashi et al, 2002 ; Casas et al, 2004 ; Cataldo et al, 2004 ), and is associated with early pathological alterations in dendrites, axonal terminals and synapses (Takahashi et al, 2004 ; Bayer and Wirths, 2010 ; Gouras et al, 2010 ).…”

Plasma Amyloid Is Associated with White Matter and Subcortical Alterations and Is Modulated by Age and Seasonal Rhythms in Mouse Lemur Primates

“…It has a short lifespan of ~12 years in captivity (Languille et al, 2012 ) and an Aβ peptide that is completely homologous to that of humans (Silhol et al, 1996 ). Approximately 10% of lemurs over 6 years old develop intracerebral Aβ deposits and their amyloid plaque load is usually low (Mestre-Frances et al, 2000 ; Kraska et al, 2011 ), though a previous study reported great heterogeneity of plasma Aβ 40 concentrations in old animals from low to high (Roy et al, 2015 ). Low plasma Aβ 40 levels in old animals have been associated with high cerebral intracellular labeling with antibodies specific of amyloid and APP (Roy et al, 2015 ).…”

“…Approximately 10% of lemurs over 6 years old develop intracerebral Aβ deposits and their amyloid plaque load is usually low (Mestre-Frances et al, 2000 ; Kraska et al, 2011 ), though a previous study reported great heterogeneity of plasma Aβ 40 concentrations in old animals from low to high (Roy et al, 2015 ). Low plasma Aβ 40 levels in old animals have been associated with high cerebral intracellular labeling with antibodies specific of amyloid and APP (Roy et al, 2015 ). As mouse lemurs can spontaneously develop age-related cerebral atrophy (Kraska et al, 2011 ; Picq et al, 2012 ; Sawiak et al, 2014 ), they are widely used to evaluate parameters modulating cerebral atrophy (Djelti et al, 2016 ).…”