Transient upregulation of translational efficiency in prodromal and early symptomatic Tg2576 mice contributes to Aβ pathology

Early-Occurring Dendritic Spines Alterations in Mouse Models of Alzheimer’s Disease Inform on Primary Causes of Neurodegeneration

“…The recent observation that polysomal APP mRNA and protein signals associate with decreased levels of the phosphorylated form of initial translation factor eIF2α, a blocker of overall translation, in 1- and 3-month-old Tg2576 mice further indicates that abnormally increased translational mechanisms sustain presymptomatic upregulation of hAPP levels in this model. Confirming that upregulation of translation contributes to AD pathogenesis, pharmacological (salubrinal) restoration of proper translational control in early symptomatic 3-month-old Tg2576 mice reverts structural and functional alterations including spine loss and prevalent LTD at CA1 hippocampal synapses, downregulates their increased levels of the β-secretase enzyme BACE-1, one main determinant of amyloidogenic APP processing, and prevents the manifestation of cognitive alterations (Borreca et al, 2020 ). Consistent with these findings, compounds like MMP13 (Zhu et al, 2019 ), which regulates BACE-1 translation, or posiphen, which decreases the production of toxic Aβ by lowering APP translation, are effective in rescuing cognitive deficits in hAPP mutant mice (Lahiri et al, 2007 ) and sporadic AD patients (Teich et al, 2018 ).…”

“…Remarkably, the addition of the Swedish transgene to the Indiana mutation increased synaptic transmission deficits. More recently, evidence has accumulated that 3-month-old hAPP mutants show a reduction in hippocampal and/or cortical spines in association with abnormal caspase-3 accumulation (D’Amelio et al, 2011 ), F -actin disassembly (Kommaddi et al, 2018 ), or upregulation of full-length APP translation (Borreca et al, 2020 ). Further support to the link between Aβ-induced alterations in the PSD network and disruption of synaptic plasticity comes from data which show that phosphorylation of the actin-binding protein cofilin-1 (pcof1) is increased in the postsynaptic enriched fraction of cortical synaptosomes of 3-month-old APP/PS1 mice.…”

ISRIB prevents synaptic plasticity disruption and cognitive deficits in live rat model of Alzheimer’s disease

“…Aberrant elevated phospho-eIF2α has been found in sporadic AD patients' brains (40)(41)(42)(43)(44)(45) and in different transgenic mouse models of AD, including APP/PS1 (8) (46), Tg2576 (42,47) and 5XFAD (43,47,48), (but see (28)). Post-mortem examination of the brains of the Aβ 1−42 injected rats showed that eIF2α phosphorylation and AFT4 were elevated by Aβ 1−42 .…”

FMRP-Driven Neuropathology in Autistic Spectrum Disorder and Alzheimer's disease: A Losing Game

“…Interestingly, protein synthesis alteration has been found also in AD brains ( Hernandez-Ortega et al, 2016 ; Cefaliello et al, 2020 ; Ghosh et al, 2020 ). Polysomal profiles from wild-type (wt) and the Tg2576 AD mouse model ( Borreca et al, 2020 ) reveals the shift of APP mRNA in the polysomal fraction, with APP more prone to be translated. Furthermore, a translational initiation factor, EIF2α is involved in AD cognitive deficit ( Costa Mattioli et al, 2006 ).…”

“…Surprisingly, in the early phase of AD, the phosphorylation status of EIF2α is reduced, suggesting an increase of protein synthesis machinery and as a consequence a compensatory mechanism taking place in the late phase of the disease with high phosphorylation status of EIF2α and block of protein synthesis. Therefore, the block of protein synthesis will occur later in the disease, possibly as a feedback control ( Borreca et al, 2020 ). Several protein synthesis molecules are involved in other neurodegenerative disorders such as EIF4G in Parkinson disease, thus suggesting a fundamental role of protein synthesis in the functional role of synapses and the cognitive deficit observed ( Dhungel et al, 2015 ).…”