Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer’s disease

Abstract

Background The degeneration of the cholinergic circuit from the basal forebrain to the hippocampus contributes to memory loss in patients suffering from Alzheimer’s disease (AD). However, the internal relationships between the acetylcholine (Ach) cycle and memory decline during the early stages of AD currently remain unknown. Here, we investigate the mechanisms underlying the activation of the cholinergic circuit and its impact on learning and memory using APP/PS1 mice models. Methods Novel object recognition and Morris water maze tests were used to measure learning and memory function. Magnetic resonance spectrum (MRS) imaging was applied to longitudinally track changes in neurochemical metabolism in APP/PS1 mice aged 2, 4, 6, and 8 months. The number of neurons and the deposition of Aβ plaques were measured using Nissl, immunohistochemistry, and Thioflavin S staining. We then employed a chemogenetic strategy to selectively activate the cholinergic circuit from the medial septal nucleus (MS) and the vertical limb of the diagonal band nucleus (VDB) on the basal forebrain to the hippocampus. MRS and immunoblotting techniques were used to measure the neurochemical metabolism levels and cholinergic-related proteins, respectively. Results We found that the levels of choline (Cho) in the basal forebrain were markedly higher compared to other brain regions and that its decrease along with N-acetyl aspartate (NAA) levels in the hippocampus was accompanied by memory deficits in APP/PS1 mice aged 4, 6, and 8 months. In terms of pathology, we observed that the deposition of Aβ plaques gradually aggravated throughout the cerebral cortex and hippocampus in APP/PS1 mice aged 6 and 8 months, while no Aβ deposition was detected in the basal forebrain. In contrast, the activity of choline acetyltransferase (ChAT) enzyme in the basal forebrain was decreased at 6 months of age and the cholinergic neurons were lost in the basal forebrain at 8 months of age. In addition, the activation of the cholinergic circuit from the MS and VDB to the hippocampus using chemical genetics is able to improve learning and reduce memory impairment in APP/PS1 mice. Similarly, the levels of Cho in the basal forebrain; NAA in the hippocampus, as well as the expression of ChAT and vesicular acetylcholine transporter (vAchT) in the basal forebrain; and muscarinic acetylcholine receptor 2 (CHRM2) in the hippocampus all increased. Conclusions These findings demonstrate that the neurochemical Cho and NAA of the cholinergic circuit can be used as biomarkers to enable the early diagnosis of AD. In addition, memory impairment in APP/PS1 mice can be attenuated using chemical genetics-driven Ach cycle activity of the cholinergic circuit.

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“…Moreover, the cholinergic system is closely related to learning and memory abilities, with a marked increase in AChE activity. 44 The activity of AChE in the brains of the model group was significantly higher than that in the control group ( p < 0.01), while it was significantly lower than that in the model group after EYVTLK, VFPTER, EPEVLR and ELEWER ( p < 0.05) intervention (Fig. 5F).…”

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“…1,2) A study using a mouse model of Aβ pathology showed that the activation of the cholinergic circuit from the basal forebrain to the hippocampus can improve the cholinergic metabolism and attenuate memory impairment in mice. 54) Therefore, early protection of cholinergic neurons in the basal forebrain is key to cure AD and elucidating the pathological mechanism underlying the cholinergic neurodegeneration induced by Aβ, especially Aβ oligomers, is expected to contribute to the development of DMTs in AD. However, the molecular mechanisms of Aβ oligomer-induced neurodegeneration in human cholinergic neurons are not fully understood due to the difficulty of handling unstable Aβ oligomers 55) and the lack of appropriate models for human cholinergic neurons.…”

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“…There are also close interactions between the loss of mitochondrial metabolism and cholinergic neuron degeneration in APP/PS1 AD mice, which, at the age of 6–8 months, displayed Aβ deposits and cognitive deficits accompanied by losses in cholinergic neurons, ChAT, VAChT, choline and NAT levels in the hippocampus and medial septum. Activation of cholinergic circuits in 4-month-old APP/PS1 AD mice with injections of M3dq virus followed by clozapine-N-oxide treatment prevented losses in cholinergic neurons and NAA levels [ 169 ]. On the other hand, activities of ChAT and levels of NAA displayed an inverse correlation in the septal and cerebellar regions of the rat brain, containing high and low densities of cholinergic neurons, respectively [ 136 , 159 ].…”