Neuronal alpha-amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology
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- Neuronal α-amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology
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Recent studies indicate a crucial role for neuronal glycogen storage and degradation in memory formation. We have previously identified alpha-amylase (alpha-amylase), a glycogen degradation enzyme, located within synaptic-like structures in CA1 pyramidal neurons and shown that individuals with a high copy number variation of alpha-amylase perform better on the episodic memory test. We reported that neuronal alpha-amylase was absent in patients with Alzheimer's disease (AD) and that this loss corresponded to increased AD pathology. In the current study, we verified these findings in a larger patient cohort and determined a similar reduction in alpha-amylase immunoreactivity in the molecular layer of hippocampus in AD patients. Next, we demonstrated reduced alpha-amylase concentrations in oligomer amyloid beta 42 (A beta(42)) stimulated SH-SY5Y cells and neurons derived from human-induced pluripotent stem cells (hiPSC) with PSEN1 mutation. Reduction of alpha-amylase production and activity, induced by siRNA and alpha-amylase inhibitor Tendamistat, respectively, was further shown to enhance glycogen load in SH-SY5Y cells. Both oligomer A beta(42) stimulated SH-SY5Y cells and hiPSC neurons with PSEN1 mutation showed, however, reduced load of glycogen. Finally, we demonstrate the presence of alpha-amylase within synapses of isolated primary neurons and show that inhibition of alpha-amylase activity with Tendamistat alters neuronal activity measured by calcium imaging. In view of these findings, we hypothesize that alpha-amylase has a glycogen degrading function within synapses, potentially important in memory formation. Hence, a loss of alpha-amylase, which can be induced by A beta pathology, may in part underlie the disrupted memory formation seen in AD patients.
Originalsprog | Engelsk |
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Artikelnummer | 13433 |
Tidsskrift | Aging Cell |
Vol/bind | 20 |
Udgave nummer | 8 |
Antal sider | 14 |
ISSN | 1474-9718 |
DOI | |
Status | Udgivet - 2021 |
ID: 275878134