TY - JOUR

T1 - Neuronal alpha-amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology

AU - Byman, Elin

AU - Martinsson, Isak

AU - Haukedal, Henriette

AU - Gouras, Gunnar

AU - Freude, Kristine K.

AU - Wennstrom, Malin

AU - Netherlands Brain Ban

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - alpha-amylases

KW - Alzheimer's disease

KW - amyloid beta-peptides

KW - calcium imaging

KW - glycogen

KW - induced pluripotent stem cells

KW - tendamistat

KW - PLURIPOTENT STEM-CELLS

KW - ALZHEIMERS-DISEASE

KW - ASTROCYTIC GLYCOGENOLYSIS

KW - L150P MUTATION

KW - DENTATE GYRUS

KW - SYNTHASE

KW - ASSOCIATION

KW - CONTRIBUTES

KW - METABOLISM

KW - GENERATION

U2 - 10.1111/acel.13433

DO - 10.1111/acel.13433

M3 - Journal article

C2 - 34261192

VL - 20

JO - Aging Cell

JF - Aging Cell

SN - 1474-9718

IS - 8

M1 - 13433

ER -