Neuronal α‐amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology

• Published in: Aging cell Vol. 20; no. 8; pp. e13433 - n/a
• Main Authors: Byman, Elin, Martinsson, Isak, Haukedal, Henriette, Gouras, Gunnar, Freude, Kristine K., Wennström, Malin
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2021; John Wiley and Sons Inc
• Subjects: alpha-Amylases - metabolism; alpha‐amylases; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; amyloid beta‐peptides; Animals; Basic Medicine; Brain; Calcium imaging; Cognitive ability; Copy number; Enzymes; Gene expression; Glucose; Glycogen; Glycogenolysis - genetics; Humans; Hypotheses; Immunoreactivity; induced pluripotent stem cells; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Memory; Metabolism; Mice; Mutation; Neurodegenerative diseases; Neurosciences; Neurovetenskaper; Original; Original Paper; Pathology; Pluripotency; Pyramidal cells; siRNA; Stem cells; tendamistat; alpha-amylases; tendamistat; induced pluripotent stem cells; amyloid beta-peptides; glycogen; Alzheimer's disease; calcium imaging
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.13433

Recent studies indicate a crucial role for neuronal glycogen storage and degradation in memory formation. We have previously identified alpha‐amylase (α‐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 α‐amylase perform better on the episodic memory test. We reported that neuronal α‐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 α‐amylase immunoreactivity in the molecular layer of hippocampus in AD patients. Next, we demonstrated reduced α‐amylase concentrations in oligomer amyloid beta 42 (Aβ42) stimulated SH‐SY5Y cells and neurons derived from human‐induced pluripotent stem cells (hiPSC) with PSEN1 mutation. Reduction of α‐amylase production and activity, induced by siRNA and α‐amylase inhibitor Tendamistat, respectively, was further shown to enhance glycogen load in SH‐SY5Y cells. Both oligomer Aβ42 stimulated SH‐SY5Y cells and hiPSC neurons with PSEN1 mutation showed, however, reduced load of glycogen. Finally, we demonstrate the presence of α‐amylase within synapses of isolated primary neurons and show that inhibition of α‐amylase activity with Tendamistat alters neuronal activity measured by calcium imaging. In view of these findings, we hypothesize that α‐amylase has a glycogen degrading function within synapses, potentially important in memory formation. Hence, a loss of α‐amylase, which can be induced by Aβ pathology, may in part underlie the disrupted memory formation seen in AD patients. Alpha‐amylase and glycogen are found in neuronal synapses. Inhibition of alpha‐amylase activity with Tendamistat increases neuronal glycogen load and causes calcium dyshomeostasis. Presence of amyloid beta is associated with reduced alpha‐amylase and glycogen load.