Perturbed glycogen metabolism is an Alzheimer’s disease therapeutic target

Abstract

AbstractBackgroundThree clinical hallmarks of AD are amyloid beta (Aβ) plaques, neurofibrillary tangles, and glucose hypometabolism. Multiple agents can decrease Aβ and tau levels, such as the recently FDA‐approved Aducanumab. However, improvements in patient cognition are disappointing and this disappointment is potentially due to a failure to normalize cerebral glucose hypometabolism.Clinical AD symptom severity strongly correlates with the degree of glucose hypometabolism. In the brain, one route of glucose metabolism is the biosynthesis of glycogen, a branched molecule that functions as an energy cache in times of energetic stress. Importantly, glycogen is critical for neuronal function and memory formation, and defective glycogen metabolism is an underlying driver of several neurological glycogen storage disorders (GSDs). An excess glycogen phenotype was reported in AD brains in the early 1980s, but to date, little is known about its involvement in AD symptoms.MethodIn this study, we first report that AD brains have an excess glycogen phenotype and that AD glycogen correlates with disease severity in human patient samples. Furthermore, the human excess AD glycogen is phenocopied in multiple AD mouse models and the accumulation of glycogen in these mice precedes cognitive deficits. Based on rigorous and striking data, we propose glycogen as a novel target for AD therapy that warrants additional preclinical development.ResultWe developed the enzyme therapy VAL‐0417 that combines a glycogen‐degrading amylase fused to an antibody fragment that facilitates intracellular delivery of recombinant enzymes. VAL‐0417 ablates excess glycogen and rescues disease phenotypes in a fatal GSD that causes childhood dementia called Lafora disease (LD). LD mice share several phenotypes with AD mouse models, including neurotoxic glycogen accumulation. Excitingly, VAL‐0417 also degrades AD glycogen both in vitro from human patient samples and in vivo in the 5xFAD AD mouse model. Furthermore, VAL‐0417 significantly reduces Ab plaque burden in 5xFAD mice and improves hippocampal long‐term potentiation.ConclusionThese studies suggest that targeting AD glycogen with VAL‐0417, either alone or in combination with other therapies targeting Aβ and/or tau, is an exciting and novel preclinical therapeutic target.