Elevated Levels of miR-144-3p Induce Cholinergic Degeneration by Impairing the Maturation of NGF in Alzheimer’s Disease

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.

Individual and Combined Associations of Glucose Metabolic Components With Cognitive Function Modified by Obesity

“…The Hisayama Study ( 35 ) reported increased odds of all-cause dementia, Alzheimer’s disease, and vascular dementia in relation to elevated 2h-PG, rather than FPG. Given the fact that memory loss is the key symptom of Alzheimer’s disease ( 36 ), our study, which showed 2h-PG negatively associated with memory, supports results derived from the Hisayama Study.…”

Electroacupuncture regulates Rab5a‐mediating NGF transduction to improve learning and memory ability in the early stage of AD mice

“…35 Additionally, the degeneration and loss of BFCNs have been described in some animal models of AD. [36][37][38][39] The hippocampus primarily receives dense cholinergic projections from the MS and VDB nuclei of the basal forebrain, forming the basal forebrain hippocampal circuit. 40 release regulates learning and memory processes by generating GABAergic inhibition of hippocampal dentate granule cells via astrocyte intermediaries.…”

“…Using post‐mortem MRI and histopathology, a recent study detected volume decrease and microstructural integrity degeneration in the nucleus basalis of Meynert (NBM) of AD patients, and the decreased BFCN density was associated with reduced cholinergic tracts to its projection cerebral areas 35 . Additionally, the degeneration and loss of BFCNs have been described in some animal models of AD 36–39 . The hippocampus primarily receives dense cholinergic projections from the MS and VDB nuclei of the basal forebrain, forming the basal forebrain hippocampal circuit 40 .…”

“… 35 Additionally, the degeneration and loss of BFCNs have been described in some animal models of AD. 36 , 37 , 38 , 39 The hippocampus primarily receives dense cholinergic projections from the MS and VDB nuclei of the basal forebrain, forming the basal forebrain hippocampal circuit. 40 Studies found that cholinergic neurons in the MS and VDB nuclei play a central role in the generation of theta‐band oscillations in the hippocampus during the process of exploration, novelty detection, and memory encoding through two anatomically and functionally distinct pathways, one is the direct MS/VDB‐hippocampal cholinergic projection and the other one is the recruitment of noncholinergic neurons within the MS and VDB nuclei.…”

A Review of miRNAs as Biomarkers and Effect of Dietary Modulation in Obesity Associated Cognitive Decline and Neurodegenerative Disorders

“…These evidence may further explore the importance of miR-144 in connection with metabolic function and neurodegenerative diseases including PD. In addition, the involvement of miR-144 in inducing cholinergic degeneration by impairing the maturation of nerve growth factor in Alzheimer's Disease has been revealed in experimental models (Zhou et al, 2021). Although more research is necessary to understand the role of miR-144, evidence from literature provides a mechanistic link of miR-144 in obesity associated neurodegenerative disorders.…”