Altered dynamics of glymphatic flow in a mature-onset Tet-off APP mouse model of amyloidosis.

BACKGROUND: Alzheimer's disease (AD) is an incurable neurodegenerative disorder characterised by the progressive buildup of toxic amyloid-beta (Aß) and tau protein aggregates eventually leading to cognitive decline. Recent lines of evidence suggest that an impairment of the glymphatic system (GS), a brain waste clearance pathway, plays a key role in the pathology of AD. Moreover, a relationship between GS function and neuronal network integrity has been strongly implicated. Here, we sought to assess the efficacy of the GS in a transgenic Tet-Off APP mouse model of amyloidosis, in which the expression of mutant APP was delayed until maturity, mimicking features of late-onset AD-the most common form of dementia in humans. METHODS: To evaluate GS function, we used dynamic contrast-enhanced MRI (DCE-MRI) in 14-month-old Tet-Off APP (AD) mice and aged-matched littermate controls. Brain-wide transport of the Gd-DOTA contrast agent was monitored over time after cisterna magna injection. Region-of-interest analysis and computational modelling were used to assess GS dynamics while characterisation of brain tissue abnormalities at the microscale was performed ex vivo by immunohistochemistry. RESULTS: We observed reduced rostral glymphatic flow and higher accumulation of the contrast agent in areas proximal to the injection side in the AD group. Clustering and subsequent computational modelling of voxel time courses revealed significantly lower influx time constants in AD relative to the controls. Ex vivo evaluation showed abundant amyloid plaque burden in the AD group coinciding with extensive astrogliosis and microgliosis. The neuroinflammatory responses were also found in plaque-devoid regions, potentially impacting brain-fluid circulation. CONCLUSIONS: In a context resembling late-onset AD in humans, we demonstrate the disruption of glymphatic function and particularly a reduction in brain-fluid influx in the AD group. We conjecture that the hindered circulation of cerebrospinal fluid is potentially caused by wide-spread astrogliosis and amyloid-related obstruction of the normal routes of glymphatic flow resulting in redirection towards caudal regions. In sum, our study highlights the translational potential of alternative approaches, such as targeting brain-fluid circulation as potential therapeutic strategies for AD.

Combining designer receptors exclusively activated by designer drugs and neuroimaging in experimental models: A powerful approach towards neurotheranostic applications.

The combination of chemogenetics targeting specific brain cell populations with in vivo imaging techniques provides scientists with a powerful new tool to study functional neural networks at the whole-brain scale. A number of recent studies indicate the potential of this approach to increase our understanding of brain function in health and disease. In this review, we discuss the employment of a specific chemogenetic tool, designer receptors exclusively activated by designer drugs, in conjunction with non-invasive neuroimaging techniques such as PET and MRI. We highlight the utility of using this multiscale approach in longitudinal studies and its ability to identify novel brain circuits relevant to behaviour that can be monitored in parallel. In addition, some identified shortcomings in this technique and more recent efforts to overcome them are also presented. Finally, we discuss the translational potential of designer receptors exclusively activated by designer drugs in neuroimaging and the promise it holds for future neurotheranostic applications.

Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. According to the amyloid hypothesis, the accumulation and deposition of amyloid-beta (Aß) peptides play a key role in AD. Soluble Aß (sAß) oligomers were shown to be involved in pathological hypersynchronisation of brain resting-state networks in different transgenic developmental-onset mouse models of amyloidosis. However, the impact of protein overexpression during brain postnatal development may cause additional phenotypes unrelated to AD. To address this concern, we investigated sAß effects on functional resting-state networks in transgenic mature-onset amyloidosis Tet-Off APP (TG) mice. TG mice and control littermates were raised on doxycycline (DOX) diet from 3d up to 3 m of age to suppress transgenic Aß production. Thereafter, longitudinal resting-state functional MRI was performed on a 9.4 T MR-system starting from week 0 (3 m old mice) up to 28w post DOX treatment. Ex-vivo immunohistochemistry and ELISA analysis was performed to assess the development of amyloid pathology. Functional Connectivity (FC) analysis demonstrated early abnormal hypersynchronisation in the TG mice compared to the controls at 8w post DOX treatment, particularly across regions of the default mode-like network, known to be affected in AD. Ex-vivo analyses performed at this time point confirmed a 20-fold increase in total sAß levels preceding the apparition of Aß plaques and inflammatory responses in the TG mice compared to the controls. On the contrary at week 28, TG mice showed an overall hypoconnectivity, coinciding with a widespread deposition of Aß plaques in the brain. By preventing developmental influence of APP and/or sAß during brain postnatal development, we demonstrated FC abnormalities potentially driven by sAß neurotoxicity on resting-state neuronal networks in mature-induced TG mice. Thus, the Tet-Off APP mouse model could be a powerful tool while used as a mature-onset model to shed light into amyloidosis mechanisms in AD.