Journal Article

DZNE-2022-00497

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Assessment of the In Vivo Relationship Between Cerebral Hypometabolism, Tau Deposition, TSPO Expression, and Synaptic Density in a Tauopathy Mouse Model: a Multi-tracer PET Study.

Endepols, H. ; Anglada-Huguet, M.DZNE* ; Mandelkow, E.DZNE* ; Schmidt, Y. ; Krapf, P. ; Zlatopolskiy, B. D. ; Neumaier, B. ; Mandelkow, E. M.DZNE* ; Drzezga, A.Extern*

2022
Humana Press Totowa, NJ

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Please use a persistent id in citations: doi:10.1007/s12035-022-02793-8

Abstract: Cerebral glucose hypometabolism is a typical hallmark of Alzheimer's disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional interrelation of glucose hypometabolism measured by [18F]FDG positron emission tomography (PET) with various molecular targets of AD pathophysiology using the PET tracers [18F]PI-2620 for tau deposition, [18F]DPA-714 for TSPO expression associated with neuroinflammation, and [18F]UCB-H for synaptic density in a transgenic tauopathy mouse model. Seven-month-old rTg4510 mice (n = 8) and non-transgenic littermates (n = 8) were examined in a small animal PET scanner with the tracers listed above. Hypometabolism was observed throughout the forebrain of rTg4510 mice. Tau pathology, increased TSPO expression, and synaptic loss were co-localized in the cortex and hippocampus and correlated with hypometabolism. In the thalamus, however, hypometabolism occurred in the absence of tau-related pathology. Thus, cerebral hypometabolism was associated with two regionally distinct forms of molecular pathology: (1) characteristic neuropathology of the Alzheimer-type including synaptic degeneration and neuroinflammation co-localized with tau deposition in the cerebral cortex, and (2) pathological changes in the thalamus in the absence of other markers of AD pathophysiology, possibly reflecting downstream or remote adaptive processes which may affect functional connectivity. Our study demonstrates the feasibility of a multitracer approach to explore complex interactions of distinct AD-pathomechanisms in vivo in a small animal model. The observations demonstrate that multiple, spatially heterogeneous pathomechanisms can contribute to hypometabolism observed in AD mouse models and they motivate future longitudinal studies as well as the investigation of possibly comparable pathomechanisms in human patients.

Keyword(s): Alzheimer Disease: diagnostic imaging (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Animals (MeSH) ; Brain: diagnostic imaging (MeSH) ; Brain: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Glucose (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Mice, Transgenic (MeSH) ; Positron-Emission Tomography: methods (MeSH) ; Receptors, GABA: metabolism (MeSH) ; Reproducibility of Results (MeSH) ; Tauopathies: diagnostic imaging (MeSH) ; Tauopathies: metabolism (MeSH) ; tau Proteins: metabolism (MeSH) ; Alzheimer’s disease ; Cerebral hypometabolism ; Microglial activation ; Neuroinflammation ; Small animal PET ; Synaptic density ; Tau

Note: (CC BY 4.0)

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Contributing Institute(s):

1. Structural Principles of Neurodegeneration (AG Mandelkow 1)
2. Cell and Animal Models of Neurodegeneration (AG Mandelkow 2)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DEAL Springer ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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