Cholinergic and inflammatory phenotypes in transgenic tau mouse models of Alzheimer’s disease and frontotemporal lobar degeneration

Abstract

An early and sizeable loss of basal forebrain cholinergic neurons is a well-characterized feature associated with measurable deficits in spatial learning and cognitive impairment in patients with Alzheimer’s disease. In addition, pro-inflammatory glial cells such as astrocytes and microglia may play a key role in the neurodegenerative cascade of Alzheimer’s disease and tauopathies. We recently presented two mouse models: Line 1, expressing the truncated tau fragment identified as the core of the Alzheimer’s paired helical filament, and Line 66, expressing full-length human tau carrying a double mutation (P301S and G335D). Line 1 mice have a pathology that is akin to Alzheimer’s, whilst Line 66 resembles frontotemporal lobar degeneration. However, their cholinergic and inflammatory phenotypes remain elusive. We performed histological evaluation of choline acetyltransferase, acetylcholinesterase, p75 neurotrophin receptor, microglial ionized calcium binding adaptor molecule 1 and astrocytic glial fibrillary acidic protein in the basal forebrain, hippocampus and cortex of these models. A significant lowering of choline acetyltransferase-positive neurons and p75-positive neurons in the basal forebrain of Line 1 at 3, 6 and 9 months was observed in two independent studies, alongside a significant decrease in acetylcholinesterase staining in the cortex and hippocampus. The reductions in choline acetyltransferase positivity varied between 30% and 50% at an age when Line 1 mice show spatial learning impairments. Furthermore, an increase in microglial ionized calcium binding adaptor molecule 1 staining was observed in the basal forebrain, hippocampus and entorhinal cortex of Line 1 at 6 months. Line 66 mice displayed an intact cholinergic basal forebrain, and no difference in p75-positive neurons at 3 or 9 months. In addition, Line 66 exhibited significant microglial ionized calcium binding adaptor molecule 1 increase in the basal forebrain and hippocampus, suggesting a prominent neuroinflammatory profile. Increased concentrations of microglial interleukin-1β and astrocytic complement 3 were also seen in the hippocampus of both Line 1 and Line 66. The cholinergic deficit in Line 1 mice confirms the Alzheimer’s disease-like phenotype in Line 1 mice, whilst Line 66 revealed no measurable change in total cholinergic expression, a phenotypic trait of frontotemporal lobar degeneration. These two transgenic lines are therefore suitable for discriminating mechanistic underpinnings between the Alzheimer’s and frontotemporal lobar degeneration-like phenotypes of these mice.

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

“…In the basal forebrain of murine models of AD, a significant loss of cholinergic neurons compared with control groups was also observed. The significant BFChN degeneration in mice matches that observed in post-mortem brains of patients with AD ( Belarbi et al, 2009 ; Cranston et al, 2020 ). Studies have shown that abnormalities in cortical cholinergic axons, such as thickening or ballooning of terminals, are present in young people, but they are more frequent in non-demented elderly people.…”

Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy

“…L66 mice overexpress the longest human tau isoform (htau40) with 441 amino acid residues, under the control of the mouse Thy1 -promoter. These mice show early onset high tau load in hippocampal and cortical neurons ( 24 ) and robust inflammation in both forebrain and hippocampal system ( 28 ) reminiscent of the behavioral variant of FTD with tau pathology. The L66 murine model has widely abundant tau pathology throughout the brain, with particularly high tau aggregation in neurons of the hippocampus and entorhinal cortex, eventually leading to neuronal loss ( 24 ).…”

Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks

“…These mice express early onset, high tau load in the brain globally and their genetics, behavioural and histopathological phenotypes are reminiscent of frontotemporal dementia. A detailed characterisation of these transgenic mice was reported earlier and male and female mice show similar behavioural and pathological phenotypes [40][41][42].…”

“…L66 harbours the FTD-associated mutation P301S in the MAPT gene. These mice show early onset high tau load in hippocampal and cortical neurons, a normal cholinergic phenotype, a robust neuroinflammation and sensorimotor and motor learning deficits [40,42]. Several of these phenotypes, including tau pathology and behavioural deficiencies, were reversed by treatment with LMTM [43,47].…”

“…We selected the line 66 (L66) mouse and compared whole brain tissue with age-matched wild-type mice using two-dimensional electrophoresis (2-DE) followed by nano liquid chromatography tandem mass spectrometry (nano-LC-ESI-MS/MS). L66 has been extensively characterised behaviourally [40], with respect to tau expression and localisation [41], in terms of cholinergic status and inflammation [42] and in synaptic release of glutamate [43]. L66 mice overexpress the largest human 2N4R isoform (441 amino acid residues) carrying aggregation-promoting mutations P301S and G335D [40,44].…”