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

Abstract

BackgroundCholinergic 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 AppNL‐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 AppNL‐G‐F mice.MethodTo ask whether AppNL‐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 AppNL‐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.ResultHistochemical analyses revealed that 24‐month‐old AppNL‐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.ConclusionThis 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 underway, and we will present these results at the meeting.

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

“…While most researchers focused on neuronal tau, Hirota et al. reported that AD‐related p‐tau181 signals localized to demyelinated axons of parvalbumin‐positive GABAergic interneurons in an App knock‐in mouse model of AD 109 . Of note, oligodendroglial tau could propagate along WM tracts, resulting in the loss of OLs.…”

“…reported that AD-related p-tau181 signals localized to demyelinated axons of parvalbumin-positive GABAergic interneurons in an App knock-in mouse model of AD. 109 Of note, oligodendroglial tau could propagate along WM tracts, resulting in the loss of OLs. Moreover, this process was independent of neuronal tau.…”