APP Deletion Accounts for Age-Dependent Changes in the Bioenergetic Metabolism and in Hyperphosphorylated CaMKII at Stimulated Hippocampal Presynaptic Active Zones

Abstract

Synaptic release sites are characterized by exocytosis-competent synaptic vesicles tightly anchored to the presynaptic active zone (PAZ) whose proteome orchestrates the fast signaling events involved in synaptic vesicle cycle and plasticity. Allocation of the amyloid precursor protein (APP) to the PAZ proteome implicated a functional impact of APP in neuronal communication. In this study, we combined state-of-the-art proteomics, electrophysiology and bioinformatics to address protein abundance and functional changes at the native hippocampal PAZ in young and old APP-KO mice. We evaluated if APP deletion has an impact on the metabolic activity of presynaptic mitochondria. Furthermore, we quantified differences in the phosphorylation status after long-term-potentiation (LTP) induction at the purified native PAZ. We observed an increase in the phosphorylation of the signaling enzyme calmodulin-dependent kinase II (CaMKII) only in old APP-KO mice. During aging APP deletion is accompanied by a severe decrease in metabolic activity and hyperphosphorylation of CaMKII. This attributes an essential functional role to APP at hippocampal PAZ and putative molecular mechanisms underlying the age-dependent impairments in learning and memory in APP-KO mice.

The causal structure of age-dependent limbic decline: fornix white matter glia damage causes hippocampal grey matter damage, notvice versa

“…Giulietti et al 45 found k f reductions in the hippocampus, temporal lobe, posterior cingulate and parietal cortex in LOAD and proposed that these changes may reflect reductions in metabolic mitochondrial activity 89 . As agerelated reductions of hippocampal metabolic activity have also been observed in animal studies 90,91 , the decline in hippocampal k f observed here may reflect reduced metabolic activity related to aging. Age-related damage to mitochondria of microglia has also been linked to sustained microglia neuroinflammation 92 .…”

Prenatal and early-life diesel exhaust exposure causes autism-like behavioral changes in mice

“…DE particles, a primary component of TRAP, have also been reported to activate microglia both in vitro and in vivo [ 6 , 89 – 91 ]. Further, developmental exposure to DE particles has been shown to increase inflammatory cytokines and alter microglia morphology in a toll-like receptor 4 (TLR4) dependent manner [ 31 ]. TLR4 has been shown to play a critical role in the maternal immune activation mouse model of autism, in which prenatal infection-induced activation of TLR4, and subsequent elevation of the key inflammatory cytokines IL6 and IL17α, are responsible for autistic-like behavior observed in pups [ 12 , 91 – 93 ].…”

“…In rodent models, hippocampal seizures, depression, and persistent cognitive effects were found when ethanol exposure occurred during this peak period of brain growth [ 29 , 30 ]. On a related note, air pollution exposure has been shown to cause a decrease in cortical thickness and lateral ventricular size in rodent models [ 10 , 31 ], suggesting that this period of intense brain growth in the third trimester may be an important window of vulnerability for neurodevelopmental toxicity related to TRAP as well. In rodents, this window of particularly robust brain growth extends into the postnatal period [ 32 , 33 ].…”

CA1 pyramidal cells have diverse biophysical properties, affected by development, experience, and aging

“…LTP can also occur following pairing of low-frequency presynaptic stimulation with postsynaptic depolarization ( Campanac & Debanne, 2008 ; Andrade-Talavera et al, 2016 ). LTP resulting from paired stimulation is one type of spike timing-dependent plasticity (STDP) in which the temporal order of spiking determines the type of plasticity induced; if presynaptic spiking occurs prior and close in time to postsynaptic spiking, then LTP occurs, while the reverse order (post →pre) produces long-term depression (LTD) ( Bi & Poo, 1998 ; Campanac & Debanne, 2008 ; Andrade-Talavera et al, 2016 ) (for reviews on STDP see Edelmann, Cepeda-Prado & Leßmann, 2017 ; Caporale & Dan, 2008 ; Dan & Poo, 2004 ). Postsynaptic stimulation can come in the form of a single spike or a burst of APs, and the relative ability of these two stimuli to induce LTP changes with age.…”