Evolution of the Aging Brain Transcriptome and Synaptic Regulation

Abstract

Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice

“…Existing evidence indicates that histone hypoacetylation mediates the silencing of neuroplasticity genes in the aging rodent's hippocampus, which is correlated with AAMI (Blalock et al 2003;Loerch et al 2008). Histone acetylation is controlled by the relative activities of histone acetyltransferases (HAT) and deacetylases (HDAC).…”

Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

“…The homologues of ApoD in Drosophila, GLaz and NLaz, protect against oxidative damage and contribute significantly to the regulation of longevity (HullThompson et al, 2009;Ruiz et al, 2011;Sanchez et al, 2006;Walker et al, 2006). ApoD is in fact the most robust age dependent up-regulated gene in the brain, conserved across species (de Magalhaes et al, 2009;Loerch et al, 2008), and its expression is boosted by a collection of traumatic, pathological and degenerative nervous system conditions in humans (reviewed by Van Dijk et al, 2006), including Parkinson's disease (Ordonez et al, 2006;Song et al, 2009).…”

Age-related changes of apolipoprotein D expression in female rat central nervous system with chronic estradiol treatment

“…Glial cells are the main cellular type involved in apo D synthesis (Boyles et al 1990b;Del Valle et al 2003;Kalman et al 2002;Navarro et al 2004;Patel et al 1995), but the number of neurons expressing apo D, also increases with aging (Belloir et al 2001;Navarro et al 1998bNavarro et al , 2010Rassart et al 2000). Control animals of 24 months show an overexpression of apo D similar to which is observed in aged humans (Kalman et al 2002;Loerch et al 2008;Navarro et al 1998bNavarro et al , 2010. In the past years, it has been proven that the absence of apo D reduces life span and, in contrast, its overexpression induces the opposite effect and increases the stress resistance (Ganfornina et al 2008;Muffat et al 2008;Sanchez et al 2006).…”

“…These observations indicate that treatment with estradiol may be able to prevent agerelated effects and neurodegenerative diseases. On the other hand, the expression of apo D increases with normal aging in all species studied (Kalman et al 2002;Loerch et al 2008;Navarro et al 1998bNavarro et al , 2010 as well as with neuropathological diseases, like Alzheimer's dementia (Belloir et al 2001;Ordoñez et al 2011;Terrisse et al 1998) or schizophrenia (Mahadik et al 2002;Thomas et al 2001a, b). Although the specific role of this apolipoprotein is unknown, studies in Drosophila (Muffat et al 2008;Sanchez et al 2006) and mouse (Ganfornina et al 2008) ascribe to apo D a key role in longevity regulation and higher survival rate, taking part in the control of lipoperoxidation.…”

“…Macroscopic and microscopic changes include a noticeable reduction in brain volume and weight, the modification of the plasmatic membrane integrity, neuronal dead, etc. The increase in the expression of apo D, related with aging, has been described by several authors (Kalman et al 2002;Loerch et al 2008;Navarro et al 2010). Variations in the apo D levels were described in tumors (Diez-Itza et al 1994;Rassart et al 2000;Søiland et al 2007), neurodegenerative diseases, as Alzheimer's (Belloir et al 2001;Navarro et al 2001Navarro et al , 2003Navarro et al , 2004Ordoñez et al 2011;Terrisse et al 1998;Thomas et al 2003) and Parkinson's diseases (Ordoñez et al 2006), as well as in different chemical and mechanical brain injuries (Montpied et al 1999;Trieu and Uckum 2000).…”