Reduced density of cholinergic fibers in App knock‐in mouse models of Aβ amyloidosis

• Published in: Alzheimer's & Dementia
• Main Authors: Hirota, Yu, Sakakibara, Yasufumi, Ibaraki, Kyoko, Takei, Kimi, Nishijima, Risa, Iijima, Koichi M., Sekiya, Michiko
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2022
• Subjects: Psychiatry and Mental health; Cellular and Molecular Neuroscience; Geriatrics and Gerontology; Neurology (clinical); Developmental Neuroscience; Health Policy; Epidemiology; Arctic
• Online Access: http://dx.doi.org/10.1002/alz.069257; https://onlinelibrary.wiley.com/doi/pdf/10.1002/alz.069257

Abstract Background Cholinergic system is critical for learning, memory, attention, and other cognitive functions. Nucleus basalis of Meynert (NBM) is a nucleus containing the cell bodies of cholinergic neurons in the brain and is severely affected by Alzheimer’s disease (AD). Significant loss of forebrain cholinergic projections is evident at prodromal stage of AD, and, along with locus coeruleus (LC), NBM neurons are among the first to display neurofibrillary tangle, suggesting that abnormality in cholinergic system is involved in the early stage of AD pathogenesis. Acetylcholinesterase inhibitors have been used for symptomatic treatment to improve cognitive function, however, mechanisms underlying neurodegeneration in cholinergic system remain elusive. We have previously reported that App NL‐G‐F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited cognitive deficits, severe neuroinflammation and significant loss of LC noradrenergic fibers accompanied by massive amyloid‐β (Aβ) pathology. In this study, we asked whether and how cholinergic system is altered in App NL‐G‐F mice. Method To ask whether App NL‐G‐F mice exhibit cholinergic degeneration, we compared the density of vesicular acetylcholine transporter (VAChT)‐positive fibers in the cortex and hippocampus as well as the number of choline acetyltransferase (ChAT)‐positive neurons in the NBM between App NL‐G‐F and wild‐type (WT) C57BL/6J mice at 24 months of age. We also examined whether tau pathology occurs in the cholinergic system in these mice. Result Histochemical analyses revealed that 24‐month‐old App NL‐G‐F mice exhibited significant decreases in the density of VAChT‐positive fibers in the cortex and the hippocampal CA1, the regions associated with learning and memory, compared to WT mice. Conclusion This study demonstrates that Aβ pathology is sufficient to reduce the density of cholinergic fibers. Quantitative analyses of cell loss and tau accumulation in ChAT‐positive neurons in the NBM are currently ...