Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice

Abstract

BackgroundAmyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer’s disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology.ResultsWe treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques.ConclusionsThis study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

The Emerging Link between O-GlcNAc and Alzheimer Disease

“…Accordingly, decreased O-GlcNAc may thus contribute to the propagation of toxic species in the brain and enable the spread of these hallmark pathologies within the AD brain. Nevertheless, regardless of the precise mechanisms that are operative, the consistent lack of apparent toxicity of OGA inhibitors (48,78,86,94,95,100), coupled with the clear protective effects of perturbing O-GlcNAc cycling, suggests that OGA inhibitors are a promising potential disease-modifying monotherapy for AD and other tauopathies. Such compounds may represent an opportunity to positively influence the toxicity associated with both tau and A␤ and accordingly alter the course of both hallmark pathologies of AD.…”

“…A recent study using bigenic TAPP mice, which manifest both amyloid and tau pathologies, reported the effects of longterm OGA inhibition using Thiamet-G (95). OGA inhibition blocked cognitive decline in these mice in parallel to decreases in A␤ levels and amyloid plaques in the brain and showed a clear trend toward decreased Sarkosyl-insoluble tau.…”

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

“…Pharmacological elevation of O‐GlcNAc levels in vivo enhances long‐term potentiation (LTP), whereas reduction in O‐GlcNAc levels blocks LTP (Tallent et al ., 2009). While upregulation of O‐GlcNAcylation pharmacologically prevents cognitive decline and memory impairment in AD transgenic mice (Kim et al ., 2013; Yuzwa et al ., 2014). In the present study, we found that PKAc is modified by O‐GlcNAc.…”

Tau: From research to clinical development

“…Another strategy uses an orally available small molecule inhibitor of O-GlcNAase (OGA) to increase O-GlcNAcylation in the brain, which has been shown by several groups to protect against tau and Ab toxicity in preclinical AD mouse models [50]. Studies in bigenic MAPT/APP mutant mice showed that inhibition of OGA prevented cognitive decline and amyloid plaque formation [51] and in JNPL3, tauopathy mice acted to block the formation of hyperphosphorylated tau, the development of tau aggregates, and neurodegeneration [52]. Various protective mechanisms are possible; however, it is interesting to note that O-GlcNAcylation of tau was recently shown to attenuate tau aggregation in vitro [53].…”