Authors: Guix, Francesc X. | Sartório, Carmem L. | ILL-Raga, Gerard
Human life unfolds not only in time and space, but also in the recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered under pathological conditions such as Alzheimer’s disease, which affects millions of people worldwide. Unfortunately, no effective cure exists to prevent this disorder, the impact of which will rise alarmingly within the next decades. While Alzheimer’s disease is largely considered to be the outcome of amyloid-β (Aβ) peptide accumulation in the brain, conceiving this complex disorder strictly as the result of Aβ-neurotoxicity is perhaps a
…too straight-line simplification. Instead, complementary to this view, the tableau of molecular disarrangements in the Alzheimer’s disease brain may be reflecting, at least in part, a loss of function phenotype in memory processing. Here we take BACE1 translation and degradation as a gateway to study molecular mechanisms putatively involved in the transition between memory and neurodegeneration. BACE1 participates in the excision of Aβ-peptide from its precursor holoprotein, but plays a role in synaptic plasticity too. Its translation is governed by eIF2α phosphorylation: a hub integrating cellular responses to stress, but also a critical switch in memory consolidation. Paralleling these dualities, the eIF2α -kinase HRI has been shown to be a nitric oxide-dependent physiological activator of hippocampal BACE1 translation. Finally, beholding BACE1 as a representative protease active in the CNS, we venture a new perspective on the cellular basis of memory, which may incorporate neurodegeneration in itself as a drift in memory consolidating systems.
Keywords: Alzheimer’s disease, β-secretase, eIF2α, exosomes, heme-regulated eIF-2α kinase, memory, nitric oxide, physiological stress response, proteolysis, translation initiation
Citation: Journal of Alzheimer's Disease Reports,
vol. 3, no. 1, pp. 113-148, 2019