Research Article: Cortical tau burden and behavioural dysfunctions in mice exposed to monosodium glutamate in early life

Date Published: August 14, 2019

Publisher: Public Library of Science

Author(s): Passainte S. Hassaan, Abeer E. Dief, Teshreen M. Zeitoun, Azza M. Baraka, Robert M. J. Deacon, Amany Elshorbagy, Hemant K. Paudel.


Although monosodium glutamate (MSG)-induced neurotoxicity has been recognized for decades, the potential similarities of the MSG model to Alzheimer’s disease (AD)-type neuropathology have only recently been investigated. MSG-treated mice were examined behaviourally and histologically in relation to some features of AD. Four-week old mice received 5 subcutaneous MSG (2 g/kg) injections on alternate days, or saline. At age 10–12 weeks, they were given a battery of behavioural tests for species-typical behaviours and working memory. The mice were killed at 12 weeks and the brains excised. Accumulation of hyperphosphorylated tau protein was assessed in cortical and hippocampal neurons by immunohistochemistry, and in cerebral cortical homogenates. A 78% increase in cortical concentrations of phosphorylated tau protein was observed in the MSG mice. Intracellular hyperphosphorylated tau immunostaining was observed diffusely in the cortex and hippocampus, together with cortical atrophic neurons, extensive vacuolation and dysmorphic neuropil suggestive of spongiform neurodegeneration. Nest-building was significantly impaired, and spontaneous T-maze alternation was reduced, suggesting defective short-term working memory. Subcutaneous MSG treatment also induced a 56% reduction in exploratory head dips in a holeboard (P = 0.009), and a non-significant tendency for decreased burrowing behaviour (P = 0.085). These effects occurred in the absence of MSG-induced obesity or gross locomotor deficits. The findings point to subcutaneous MSG administration in early life as a cause of tau pathology and compromised species-typical behaviour in rodents. Determining whether MSG can be useful in modelling AD requires further studies of longer duration and full behavioural characterization.

Partial Text

Alzheimer’s disease (AD) is the most common cause of dementia, a devastating condition affecting 50 million people worldwide, and causing significant disability and dependency [1]. Aggregation of intraneuronal hyperphosphorylated forms of the microtubule-associated tau protein in the form of neurofibrillary tangles is a hallmark of the disease, and parallels cognitive dysfunction in AD patients [2,3]. To date, there is no treatment for AD, despite some successes in preventive strategies [4]. Numerous transgenic and pharmacologic animal models of AD have been developed to test potential treatments, but a perfect model capturing all AD features remains elusive [5].

Impairment of short-term memory, and β-amyloid accumulation in the hippocampus, both characteristic of AD, were previously seen in adult rats treated neonatally with MSG [7]. In the present study in mice, we further characterized the MSG neurotoxic model with respect to AD-type tau pathology and effects on species-typical behaviours. MSG-treated mice exhibited diffuse cortical and hippocampal intraneuronal accumulation of hyperphosphorylated tau, with widespread spongiform degeneration and neuronal atrophy. MSG also induced impairments in short-term working memory, nest building and exploratory behaviour. These findings point to MSG as one of the neurotoxins causing AD-like pathology, and raise the question of whether phosphotau accumulation partly underlies some of the previously reported neurological deficits caused by MSG.

MSG administration in early life in mice induced accumulation of hyperphosphorylated tau in the cortex and hippocampus, with diffuse vacuolar changes and neuronal atrophy. These structural abnormalities were associated with impairment of short term-memory and some species-typical behavioural tasks, but not with obesity or locomotor deficits. The findings point to MSG as one of the causes of tau pathology and compromised species-typical behaviour. However, determining whether MSG can be useful in mimicking AD requires further studies of longer duration and fuller behavioural characterization.