MicroRNA-132 and early growth response-1 in nucleus basalis of Meynert during the course of Alzheimer’s disease

Abstract

The cholinergic nucleus basalis of Meynert, which is important for memory functions, shows neuronal activation ('up-phase') during the early stages of Alzheimer's disease and neurodegeneration ('down-phase') in later stages of Alzheimer's disease. MicroRNA-132 (miR-132) and the transcription factor early growth response-1 (EGR1) were proposed as possible candidate molecules regulating such an up-down activity pattern of the nucleus basalis of Meynert during the course of Alzheimer's disease, as they both show this up-down pattern of expression in the prefrontal cortex during the course of Alzheimer's disease. Not only do these two molecules stimulate synaptic activity and plasticity, they are also involved in Alzheimer's disease pathology and might, in addition, affect cholinergic function. In the nucleus basalis of Meynert, we investigated the expression of miR-132 and EGR1 along the entire course of Alzheimer's disease. Forty-nine post-mortem nucleus basalis of Meynert samples were studied, ranging from non-demented controls (Braak stage = 0) to late Alzheimer's disease patients (Braak stage = VI), and from clinical Reisberg scale 1 to 7. Each Braak stage contained seven samples, that were all well matched for confounding factors, i.e. age (range 58-91), sex, post-mortem delay, cerebrospinal fluid pH (as a measure for agonal state), APOE genotype, clock time of death, tissue fixation time, and tissue storage time. The alterations of these two molecules were studied over the course of Alzheimer's disease in relation to the expression of 4G8-stained amyloid-β, hyperphosphorylated tau stained by antibody AT8, neuronal fibrillary tangles and neuropil threads stained by silver, and in relation to alterations in choline acetyltransferase. We found that the expression of miR-132 and EGR1 in the nucleus basalis of Meynert was quite stable during the early stages of Alzheimer's disease and decreased significantly only during late Alzheimer's disease stages. In addition, miR-132 and EGR1 showed a significant positive correlation with choline acetyltransferase expression (r = 0.49, P < 0.001 and r = 0.61, P < 0.001), while choline acetyltransferase expression showed a significantly negative correlation with hyperphosphorylated tau (r = -0.33, P = 0.021) but no correlation with 4G8-stained amyloid-β. From the functional changes of miR-132 and EGR1 along the course of Alzheimer's disease we conclude: (i) that these two molecules may play a role in keeping the cholinergic function intact in early Alzheimer's disease stages; and (ii) that these molecules may contribute to the late neurodegeneration of this cholinergic nucleus.

microRNA‐132: a key noncoding RNA operating in the cellular phase of Alzheimer's disease

“…Distinct technological platforms, different tissue repositories, variable postmortem interval to sample storage, divergent processing protocols, and inadequate sample size may all introduce bias into the publically available datasets. Nevertheless, miR-132 deficiency has been consistently reported in the context of neurodegeneration (13), supporting the significance of miR-132 in the pathogenic processes of sporadic, lateonset AD (6)(7)(8)(9)(10)(11)(12), PD (14), HD (15), ALS (16), frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP) inclusions (17), Pick's disease, progressive supranuclear palsy (PSP) (8), prion diseases (18), and spinal muscular atrophy (SMA; summarized in Table 1).…”

“…Context specificity could account for the differential regulation of mouse and human TAU by miR‐132 and for the disparate effects on TAU expression observed on miR‐132 genetic knockout or acute knockdown. In contrast, an indirect effect of miR‐132 on TAU phosphorylation has been established more conclusively: miR‐132 expression levels and hyperphosphorylated TAU aggregates inversely correlate in the brain of patients with AD and in AD mouse models (7, 10, 11, 56). This could be possibly explained by up‐regulation of other predicted miR‐132 targets, such as the kinases cyclin‐dependent kinase 5, glycogen synthase kinase 3 b (GSK3B), MAPK1 (ERK2), and MAPK3 (ERK1), all of which have been implicated in aberrant TAU phosphorylation and neurofibrillary tangle formation in AD (58).…”

“…In AD, which is the focus of the current review, miR-132, which is, as we will discuss below, involved in various aspects of CNS function, exhibits robust and consistent down-regulation before widespread neuronal loss occurs (6)(7)(8)(9)(10)(11)(12). This sets it apart from many other miRNAs whose differential expression among AD and healthy control samples was not consistently reproduced (7,13).…”

Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

“…However, a deeper understanding of the molecular regulators of AHN, and especially a better understanding of the molecular mechanisms going astray in disease, are a prerequisite for considering restoring AHN as a therapeutic strategy for neurodegenerative diseases. Previously, we and other have shown that miR-132 is strongly and reproducibly downregulated in the hippocampus of AD patients, notably early during disease progression (Hebert et al, 2013; Lau et al, 2013; Patrick et al, 2017; Pichler et al, 2017; Salta and De Strooper, 2017; Salta et al, 2016; Smith et al, 2015; Wong et al, 2013; Zhu et al, 2016). miR-132 overexpression in primary neurons or mouse brain represses pathological hallmarks of AD, such as amyloid plaques, TAU hyperphosphorylation and deposition, and neuronal death (El Fatimy et al, 2018; Hernandez-Rapp et al, 2015; Salta et al, 2016; Smith et al, 2015; Wang et al, 2017; Wong et al, 2013; Zhu et al, 2016) (reviewed in (Salta and De Strooper, 2017)).…”

“…This observation is in line with recent reports providing strong evidence for decreased AHN in AD (Moreno-Jiménez et al, 2019; Tobin et al, 2019). Hence, miR-132 deficiency in the hippocampus of AD patients (Hebert et al, 2013; Lau et al, 2013; Patrick et al, 2017; Pichler et al, 2017; Salta and De Strooper, 2017; Salta et al, 2016; Smith et al, 2015; Wong et al, 2013; Zhu et al, 2016) is correlated with the decreased proliferation of neuronal precursors in the dentate gyrus.…”