Alzheimer's disease: targeting the glutamatergic system

Abstract

Alzheimer's disease (AD) is a debilitating neurodegenerative disease that causes a progressive decline in memory, language and problem solving. For decades mechanism-based therapies have primarily focused on amyloid β (Aβ) processing and pathways that govern neurofibrillary tangle generation. With the potential exception to Aducanumab, a monotherapy to target Aβ, clinical trials in these areas have been challenging and have failed to demonstrate efficacy. Currently, the prescribed therapies for AD are those that target the cholinesterase and glutamatergic systems that can moderately reduce cognitive decline, dependent on the individual. In the brain, over 40% of neuronal synapses are glutamatergic, where the glutamate level is tightly regulated through metabolite exchange in neuronal, astrocytic and endothelial cells. In AD brain, Aβ can interrupt effective glutamate uptake by astrocytes, which evokes a cascade of events that leads to neuronal swelling, destruction of membrane integrity and ultimately cell death. Much work has focussed on the post-synaptic response with little insight into how glutamate is regulated more broadly in the brain and the influence of anaplerotic pathways that finely tune these mechanisms. The role of blood branched chain amino acids (BCAA) in regulating neurotransmitter profiles under disease conditions also warrant discussion. Here, we review the importance of the branched chain aminotransferase proteins in regulating brain glutamate and the potential consequence of dysregulated metabolism in the context of BCAA or glutamate accumulation. We explore how the reported benefits of BCAA supplementation or restriction in improving cognitive function in other neurological diseases may have potential application in AD. Given that memantine, the glutamate receptor agonist, shows clinical relevance it is now timely to research related pathways, an understanding of which could identify novel approaches to treatment of AD.

Keywords: Aging; Alzheimer's disease; BCAT; Branched chain amino acids; Glutamate.

Fig. 1

Amyloid precursor protein processing pathways.APP undergoes either α or β secretase processing generating the secretory APPα subunit or the secretory APP β subunit, respectively. Subsequent cleavage by γ-secretase generates the p3 peptide and Aβ for the amyloidogenic and non-amyloidogenic pathway, respectively. (Moraes and Gaudet 2018) with permission from Oxford University Press

Fig. 2

BCAT metabolism in the human brain. Leucine (∆) readily crosses the blood brain barrier and undergoes BCATc transamination in neuronal cells producing glutamate. Excess glutamate generated during excitation is taken up by astrocytes, where glutamate is regenerated through the glutamate/glutamine cycle. Glutamate may also be removed by endothelial cells of the vasculature. (Image generated using BioRender)

Fig. 3

Branched chain amino acid (BCAA) oxidation. Transamination of the BCAAs, leucine, isoleucine and valine with α-keto glutarate forming the respective α-keto acids, (BCKAs: α-ketoisocaproate (KIC), α-keto-β-methylvalerate (KMV) and α-ketoisovalerate (KIV)) and glutamate, regenerating the enzyme. Subsequent oxidation by the branched chain α-keto acid dehydrogenase complex generates the branched chain acyl CoA, which enter the TCA cycle. Glutamate can be further metabolised by glutamate dehydrogenase to generate glutamine. (Adapted from Conway and Hutson 2016)

Fig. 4

Medulla BCATc and BCATm staining. a BCATc staining of the inferior olivary nucleus. b Antigen incubation of serial section, at 200× molar excess. c Increased magnification of the inferior olivary nucleus showing staining of small neurons (large arrow) and neuropil staining (small arrow) along with immunonegative hylum (*). d BCATm staining of the inferior olivary nucleus. e Antigen incubation of serial section, at 200× molar excess. f Vessel staining (*) within the amiculum of the inferior olivary nucleus. Scale bar: a, b, d and e 200 μm; c and f 100 μm. (Hull 2012)

Fig. 5

Increased hBCATc expression in the hippocampus of AD brains. CA4 region of the hippocampus in a control (a) and AD brain (b) showing intensely labelled neurons (large arrows) and the granule cell layer (dotted line). CA1 region of the hippocampus in a control (e) and AD (f) subject showing intensely labelled neurons (large arrows). c, d, g, h The slides were scored on a 0–3 scoring system and analyzed for significance using the Wilcoxon-Mann-Whitney test in Minitab™ as described in materials and methods. i Western blot analysis of hippocampal tissue. The density of each band was measured using ImageJTM software (Wayne Rasband, National Institute of Health, USA) and analyzed for significance using a one-way ANOVA test in Minitab™. j Interquartile range (box) sample variability (whiskers) and the median (horizontal line within the interquartile range) are shown. Magnification for a, b, e, and f, ×10. Scale bar: 200 μm. (Reprinted from Hull et al. (2015a) with permission from IOS Press)

Fig. 6

BCAT metabolism in the human brain. Under conditions where excitotoxicity persists, astrocytes are ineffective at clearing excess glutamate. This results in the post synaptic overstimulation of NMDA receptors causing calcium overload and ROS-related cell death. Moreover, levels of BCATc are increased in glutamatergic neurons, increasing the synthesis of glutamate, exacerbating neuronal toxicity. (Image generated using BioRender)