Lowering glucose enhances BACE1 activity and Aβ generation in mouse brain slice cultures

Numerous environmental risk factors are now recognised as contributors to the onset and progression of Alzheimer’s disease (AD). It is probable that, in most instances, AD arises from a combination of genetic predisposition and environmental influences. In particular, there is a strong correlation between vascular impairment and dementia, yet the specific mechanisms by which vascular impairment and AD are linked, remain unknown. Hypoglycaemia can occur both due to vascular impairment, and due to fluctuating glucose levels in the context of diabetes, another risk factor for AD, and could potentially be involved in disease pathogenesis. To assess whether low glucose could contribute to the build-up of brain amyloid-β (Aβ) seen in AD, we exposed wildtype mouse organotypic hippocampal slice cultures (OHSCs) to varying glucose concentrations. Lowering glucose levels leads to an elevation in both Aβ1-42 and Aβ1-40 secreted into the culture medium, accompanied by an increased accumulation of Aβ within the slice tissue. This effect is replicated in OHSCs derived from the TgCRND8 mouse model of overexpressed, mutant APP and in human SH-SY5Y cells. The heightened Aβ levels are likely attributed to an upregulation of BACE1 activity, which is also observed with lowered glucose levels. In contrast, OHSCs subject to hypoxia exhibited no alterations in Aβ levels whether singularly, or in combination of hypoglycaemia. Finally, we found that alternative energy sources such as pyruvate, fructose 1,6-bisphosphate, and lactate can alleviate heightened Aβ levels, when given in combination with lowered glucose. This study underscores the capacity to induce an increase in Aβ in a wildtype ex vivo system by selectively decreasing glucose levels. ### Competing Interest Statement The authors have declared no competing interest. * Aβ : amyloid-β ACE : angiotensin-converting enzyme AD : Alzheimer’s disease APP : amyloid precursor protein BACE1 : β-site APP Cleaving Enzyme 1 CTSB1 : cathepsin B 1 CTSB2 : cathepsin B 2 CTSD1 : cathepsin D 1 FBP : fructose 1,6-bisphosphate IDE : insulin-degrading enzyme MME : membrane metallo-endopeptidase NFTs : neurofibrillary tangles OHSC : organotypic hippocampal slice culture WT : wildtype