The hypothalamus as the primary brain region of metabolic abnormalities in APP/PS1 transgenic mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an amyloid-related neurodegenerative disorder and is also considered to be a metabolic disease. Thus, investigation of metabolic mechanisms of amyloid pathology progression is of substantial importance for the diagnosis, prevention and treatment of AD. In the present study, cognitive function and brain metabolism were explored in the transgenic APP/PS1 mouse model of amyloid pathology at different ages. Using an NMR-based metabolomic approach, we examined metabolic changes in six different brain regions of wild-type and APP/PS1 mice at 1, 5 and 10months of age. Learning and memory performance in mice was evaluated using the Morris water maze test. Furthermore, a generalized linear mixed model was employed to analyze the interaction effect between the mouse-type and brain region (or age) on metabolic alterations. Brain region-specific changes in energy metabolism occurred prior to a very early-stage of amyloid pathology (1month of age) in APP/PS1 mice. A hypermetabolic state was identified in the brains of APP/PS1 mice at 5months of age, and the hypothalamus was identified as the main brain region that underwent significant metabolic alterations. The cognitive function of APP/PS1 mice was impaired at 10months of age; moreover, the hypermetabolic state identified in various brain regions at 5months of age was also significantly decreased. In conclusion, our results suggest that a hypothalamic metabolism abnormality may comprise a potential indicator for the early-diagnosis and monitoring of amyloid pathology progression.

Decreased salivary lactoferrin levels are specific to Alzheimer’s disease

“…Therefore, it is remarkable that salivary Lf levels will not decrease in other dementia such as FTD. A possible explanation could be that the hypothalamic region, that controls body innate immunity, [49] is affected in AD [50][51][52][53], but not in FTD. In addition to amyloid plaques and neurofibrillary tangles, functional studies suggest that hypothalamic dysfunction is a common event in AD, often early in the course of disease [51].…”

“…The secretion of salivary proteins is controlled by cholinergic parasympathetic nerves that release acetylcholine, evoking the secretion of saliva by acinar cells in the salivary gland [55]. These parasympathetic nerves are connected with the hypothalamus [50][51][52][53]. We propose that early hypothalamic Aβ accumulation may disrupt hypothalamic function affecting salivary gland regulation that ultimately results in reduced salivary Lf secretion.…”

Brain-Region Specific Metabolic Abnormalities in Parkinson’s Disease and Levodopa-Induced Dyskinesia

“…1 H-NMR based metabolomics has proven to be a key for the characterization of metabolic profiles relevant to brain function and disease (Ivanisevic and Siuzdak, 2015). Our previous studies demonstrated that metabolic abnormalities in the brain participated in DM-associated cognitive dysfunction (Zheng et al, 2017) and pathogenesis of Alzheimer's disease (Zheng et al, 2018b). And increasing evidence in recent researches has supported the idea that metabolic abnormality may be causal to PD and LID, though it is unclear how metabolic disruption affects striatal activity in vivo.…”

Role of sex and high fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer’s disease

“…Neuroimaging studies report decreases in hypothalamic volume/gray matter [16][17][18], perfusion [19,20], and glucose metabolism [21] in MCI and/or AD patients. Abnormalities in hypothalamic metabolism and cerebral blood flow have also been seen in a mouse model of AD, observed prior to disturbances in the hippocampus and the onset of cognitive decline [22,23]. Additionally, previous studies suggest that AD pathology may attenuate central responsivity to peripheral metabolic signals.…”