Abstract
Cholinergic degeneration is one of the key pathological hallmarks of Alzheimer’s disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons. The trophic effects of NGF rely on the appropriate maturation of NGF from its precursor, proNGF. The ratio of proNGF/NGF is known to be increased in patients with AD; however, the mechanisms that underlie this observation have yet to be elucidated. Here, we demonstrated that levels of miR-144-3p are increased in the hippocampi and the medial prefrontal cortex of an APP/PS1 mouse model of AD. These mice also exhibited cholinergic degeneration (including the loss of cholinergic fibers, the repression of choline acetyltransferase (ChAT) activity, the reduction of cholinergic neurons, and an increased number of dystrophic neurites) and synaptic/memory deficits. The elevated expression of miR-144-3p specifically targets the mRNA of tissue plasminogen activator (tPA) and reduces the expression of tPA, thus resulting in the abnormal maturation of NGF. The administration of miR-144-3p fully replicated the cholinergic degeneration and synaptic/memory deficits observed in the APP/PS1 mice. The injection of an antagomir of miR-144-3p into the hippocampi partially rescued cholinergic degeneration and synaptic/memory impairments by restoring the levels of tPA protein and by correcting the ratio of proNGF/NGF. Collectively, our research revealed potential mechanisms for the disturbance of NGF maturation and cholinergic degeneration in AD and identified a potential therapeutic target for AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia (Alzheimer’s Disease Facts and Figures, 2020)
To investigate cholinergic dysfunction in a mouse model of AD, we first performed immunohistochemistry with an anti-choline acetyltransferase (ChAT) antibody to identify cholinergic fibers in the hippocampi and the medial prefrontal cortex, the two major regions of the brain that were projected from basal forebrain cholinergic neurons (BFCNs) (Ballinger et al, 2016)
We found that the intensity of ChAT immunostaining was dramatically reduced in the hippocampi of 12-monthsold AD mice when compared to that in the age-matched C57 controls (Figures 1A,B), indicating the loss of cholinergic fibers in AD
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia (Alzheimer’s Disease Facts and Figures, 2020). Only five drugs have been approved by the Food and Drug Administration (FDA) for the therapy of AD; three of these (donepezil, galantamine, and rivastigmine) are cholinesterase inhibitors, suggesting that cholinergic dysfunction plays a critical role in the progression of AD. In the brain of aged AD transgenic mice (Tg2576), researchers observed strong staining of acetylcholinesterase (AChE) associated with dystrophic fibers within cholinergic projections (Apelt et al, 2002). All of these abnormalities in the cholinergic systems show strong correlations with impaired synaptic/memory in AD (Oda, 1999). It is important to investigate the precise mechanisms that cause such cholinergic dysfunction
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
