BACE1 Translation: At the Crossroads Between Alzheimer’s Disease Neurodegeneration and Memory Consolidation

Abstract

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 eIF2 α phosphorylation: a hub integrating cellular responses to stress, but also a critical switch in memory consolidation. Paralleling these dualities, the eIF2 α -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.

Unveiling OASIS family as a key player in hypoxia–ischemia cases induced by cocaine using generative adversarial networks

“…This is probably due to the common symptom of cocaine intake, which reduces nitric oxide (NO). Since Hri activation depends on NO binding 43 , 44 , this inhibition of Hri (Fig. 3 d) is responsible for the conditions of HI.…”

Lowering glucose enhances BACE1 activity and Aβ generation in mouse brain slice cultures

“…The sequential cleavage of APP by β-then γ-secretases gives rise to Aβ, with BACE1 (β-site APP Cleaving Enzyme 1), the β-secretase responsible for APP cleavage, considered the rate-limiting step in its synthesis. Post mortem analysis shows an upregulation of BACE1 in the AD brain [36]. Both oxidative stress and inflammation are characteristics of AD, and are known to increase BACE1 expression and activity [37–39].…”

Berberine Reduces Aβ42 Deposition and Tau Hyperphosphorylation via Ameliorating Endoplasmic Reticulum Stress

“…NFTs comprise hyperphosphorylated tau protein, and the tau protein is phosphorylated by several kinases, including glycogen synthase kinase 3b (GSK3β), forming matured and stable microtubules ( Tiwari et al, 2019 ). The production of senile plaques and hyperphosphorylated tau is triggered by different signals, wherein the recent studies have indicated several overlapping manifestations between these two ( Chauhan and Chauhan, 2006 ; Long and Holtzman, 2019 ), which also includes endoplasmic reticulum stress (ER stress) ( Salminen et al, 2009 ; Guix et al, 2019 ).…”