Loss of Medial Septum Cholinergic Neurons in THY-Tau22 Mouse Model: What Links with tau Pathology?

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, the mechanisms underlying cholinergic neurons degeneration remain uncertain. The present study aimed to investigate the relationship between neurofibrillary degeneration and cholinergic defects in AD using THY-Tau22 transgenic mouse model exhibiting a major hippocampal AD-like tau pathology and hyperphosphorylated tau species in the septohippocampal pathway. Here, we report that at a time THY-Tau22 mice display strong reference memory alterations, the retrograde transport of fluorogold through the septohippocampal pathway is altered. This impairment is associated with a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum. Analysis of nerve growth factor (NGF) levels supports an accumulation of the mature neurotrophin in the hippocampus of THY-Tau22 mice, consistent with a decrease of its uptake or retrograde transport by cholinergic terminals. Finally, our data strongly support that tau pathology could be instrumental in the cholinergic neuronal loss observed in AD.

Microstructural White Matter Changes, Not Hippocampal Atrophy, Detect Early Amnestic Mild Cognitive Impairment

“…Meanwhile, anterograde axonal transport of cholinergic inputs from the basal forebrain to the hippocampus via the fornix facilitates production of brain-derived neurotrophic factor (BDNF) and its associated growth and proliferation of neurons in the hippocampus [61], [62]. Therefore, primary fornical abnormalities due to defective axonal transport might drive and promote downstream neuronal loss in the basal forebrain [63] and the hippocampus [64], which is supported by our finding that fornical degradation occurred with no evidence of hippocampal atrophy in the early aMCI group and loss of fornical WM integrity correlated with hippocampal atrophy in late aMCI individuals.…”

Interactions between Aβ oligomers and presynaptic cholinergic signaling: Age-dependent effects on attentional capacities

“…Therefore, development of drugs targeting Aβ oligomers may hold promise to restore presynaptic cholinergic transmission and decline in attentional capacities in early AD. As abnormal tau phosphorylation is also induced by Aβ oligomers [70-72], and this pathological feature is also linked to cholinergic atrophy during the later stages of AD [73], therapeutic approaches that detoxify oligomeric Aβ may also offer tremendous potential to slow down the disease progression and cholinergic dysfunction with age.…”

Human platelet concentrates: a source of solvent/detergent‐treated highly enriched brain‐derived neurotrophic factor

“…Mouse hippocampus was prepared as described in previous research 34 . Briefly, after the animal was killed, the hippocampus was homogenized with Teflon potter in 300 µL of ice‐cold RIPA buffer (Pierce, Thermo Fisher Scientific, Brebières, France) supplemented with 0.5% CHAPS (Amersham Biosciences, Saclay, France), protease inhibitors (Complete, Roche Diagnostics, Meylan, France), and phosphatase inhibitors (125 nmol/L okadaic acid and 1 mmol/L sodium orthovanadate, Sigma Chemical Co.).…”