Huggenberger S, et al., J Alzheimer’s Neurodegener Dis 2021, 7: 051 DOI: 10.24966/AND-9608/100051
HSOA Journal of
Alzheimer’s & Neurodegenerative Diseases Short Communication
Longitudinal Assessment of tau Phosphorylation in the Brainstem of P301L tautransgenic pR5 Mice Stefan Huggenberger1,2,#,*, Mario Paterno2,#, Kerstin Morcinek2, Lennart Müller-Thomsen1, Brigitte Dawidowski2 and Hannsjörg Schröder2 Institute of Anatomy and Clinical Morphology, Witten/Herdecke University, Alfred-Herrhausen-Straße 50, 58448 Witten, Germany
1
Department II of Anatomy (Neuroanatomy), University of Cologne, 50924 Cologne, Germany
2
#
Equal Contribution
Abstract The pR5 mouse displays tau-hyperphosphorylation in multiple brainstem nuclei. Here we show a massive tau-phosphorylation in several nuclei of adult pR5-mice (6 to 18 months) including the motor nucleus of the trigeminal nerve (5N) which, however, did not contain neurofibrillary tangles. Body weights of pR5 mice was found to be significantly lower than in littermates. Since the 5N innervates the masticatory muscles an impaired chewing function may lead to lesser body weight of pR5 mice. Body weight loss is well known to accompany Alzheimer’s disease in humans and, so far, one study indicated tau-hyperphosphorylation in the 5N of Alzheimer’s patients. Keywords: Alzheimer’s disease; Human P301L tau protein; Trigeminal nuclei; Masticatory muscles; Body weight; Tauhyperphosphorylation
Introduction To date, studies of neurofibrillary disorders focused mainly on the telencephalon in both humans and animal models [1-4]. This is due to *Corresponding author: Stefan Huggenberger, Institute of Anatomy and Clinical Morphology, Witten/Herdecke University, Alfred-Herrhausen-Straße 50, 58448 Witten, Germany; E-mail: stefan.huggenberger@uni-wh.de Citation: Huggenberger S, Paterno M, Morcinek K, Müller-Thomsen L, Dawidowski B, et al. (2021) Longitudinal Assessment of tau Phosphorylation in the Brainstem of P301L tau-transgenic pR5 Mice. J Alzheimers Neurodegener Dis 7: 051. Received: March 01, 2021; Accepted: March 16, 2021; Published: March 23, 2021 Copyright: © 2021 Huggenberger S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
the fact that the cardinal symptoms of many human neurodegenerative diseases are related to memory and cognitive dysfunction [5]. Comparatively few data are available for the human [6-11] and animal brainstem [12-14]. This is surprising since it is known for disorders such as Alzheimer’s disease (AD) that brainstem-related symptoms like dysphagia [15] appear rather early in the course of the disease. Furthermore, weight loss in elderly patients has been described as a marker for mild cognitive impairment (MCI) [16], preclinical AD [17] and a decreased body mass-index (BMI) as associated with cerebral AD pathology [18,19]. Among the spectrum of AD symptoms, nutrition-related problems are of similar importance as cognitive disturbances [20]. In terms of disease development progression, the supratrochlear subunit of the dorsal raphe magnus nucleus is affected by neurofibrillary tangle (NFT) formation well before the transentorhinal stage [21]. In particular the finding of intraneuronal pretangle material in the locus caeruleus of children and young adults suggests that the pathologic process leading to tau pathology may begin in selected brainstem nuclei [21] and is then propagated to other brain areas [22,23]. Accordingly, studies in early stages of AD found considerable involvement of brainstem nuclei (reviewed in [24]). Aside from that, Wai et al. [11] described tau-hyperphosphorylation in the motor nucleus of the trigeminal nerve of patients with AD. In line with these studies, studies from our laboratory had shown that in aged pR5 mice a number of brainstem nuclei show tau-hyperphosphorylation [13]. Based on this study [13] and the human findings described above we have chosen the motor nucleus of the trigeminal nerve (5N) for a longitudinal study (8, 16 and 19 months of age). This cholinergic nucleus, which innervates the mouse masticatory muscles [25], shows pronounced tau-hyperphosphorylation [13]. Here, we have examined the 5N in detail and selected body weight as a simple functional parameter. Moreover, the longitudinal development of tau-hyperphosphorylation has been assessed for the entire brainstem. The data were presented in parts as poster presentation at the 14th International Conference on Alzheimer’s and Parkinson’s Diseases [26].
Materials and Methods Male tau tg pR5 mice [27] and gender- and age-matched nontransgenic (non-tg) littermates were used for controlling body weight and health status at the age of 6 (n=11), 14 (n=10) and 17.5 (n=11) months. Out of these mice, coronal brainstem sections (5 µm) of 13 mice at the age of 8 (n=3 pR5 mice), 16 (n=3 pR5 mice) and 19 (n=3 pR5 mice) months were made. The animals were housed under a 12h light-dark cycle with food and water ad libitum. The P301L tau transgenic pR5 mouse with neuronal expression of the longest human tau (HT) isoform was generated on a C57BL/6 background. The tau filament formation was accomplished by the missense mutation P301L in exon 10, known from frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Experiments were approved by the governmental animal care and use office (Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen,