The Neuroscientist Comments

Abstract

For more than a century, neuroscience was permeated by a key dogma, positing that the adult mammalian brain was characterized by an absence of neurogenesis, so that it lacked the formation of new neuronal cells. This view was based on the belief that the adult brain is a static network requiring a substantial stability among neuronal connections whose modulation might result in behavioral or cognitive changes. This belief was finally challenged in the mid-1960s when it was discovered that new neurons are born in the adult hippocampus of rodents. Over the following decades, neurogenesis was demonstrated to occur in the brain of several mammals, including humans. Work in animal models and humans has provided evidence that adult hippocampal neurogenesis plays an important role in memory formation. Furthermore, it has been shown that, while new immature neurons can be found in neurologically healthy human subjects up to the ninth decade of life, the number and maturation of these neurons progressively declines in Alzheimer’s disease (AD) as a function of disease progression (MorenoJiménez and others 2019). Cumulative data have demonstrated adult neurons born at the subgranular zone of the dentate gyrus of the hippocampus in a wide range of physiological mnemonic processes. For instance, pattern separation, a memory function that enables separation of similar representations into distinct, nonoverlapping memories, has been shown to be causally linked to adult hippocampal neurogenesis (AHN) and is functionally dependent on the adult-born neurons in the rodent dentate gyrus. Interestingly, several studies showed impaired pattern separation abilities in patients in prodromal and late stages of AD. In terms of AD treatment, after two decades of failures in key clinical trials, the Food and Drug Administration recently approved Biogen’s Aduhelm (Aducanumab). While this decision met with controversy, it represents the first novel therapy approved for AD since 2003. Moreover, Novak and coworkers recently published the positive results of a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in AD (Novak and others 2021). Despite these advances, disease-modifying drugs for AD are an urgent and unmet need. As such, a deeper understanding of the molecular mechanisms involved in AHN becomes particularly relevant when considering it as a therapeutic target for AD. Against this background, miR-132, a short noncoding RNA molecule that arises from the miR-212/132 cluster located in the intron of a noncoding gene on mouse chromosome 11, is considered one of the most consistently downregulated microRNAs in AD, and is a strong regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny. Previous studies (Salta and others 2014) have shown that miR-132 regulates the timing for cell cycle exit of radial glia-like (RGL) neural stem cells in the developing vertebrate spinal cord. Much less is known about the role of miR-132 in adult rodent and human dentate gyrus although miR-132 deletion in adult dentate gyrus has been shown to induce significant alterations in neurite maturation, spine formation, and synaptic activity of newborn neurons, thus compromising their functional integration into the adult hippocampal circuitry (Luikart and others 2011). Crucially, miR-132 overexpression in primary neurons or mouse brain limits pathological hallmarks of AD, such as amyloid plaques, TAU hyperphosphorylation and deposition, and neuronal death (El Fatimy and others 2018). In their very recent study, Walgrave and coworkers (2021) report that miR-132 regulation plays a key role in AHN. They present evidence that miR-132 replacement restores AHN and memory deficits in two distinct mouse models of AD by exerting diverse effects at the adult hippocampal neurogenic niche. These authors employed an array of experiments and methodological approaches, including two distinct animal models (one co-expressing human-mutated APPSwe [KM670/671NL APP] and human mutated presenilin 1 [L166P], and the other expressing APP KM670/671NL [Swedish], APP I716F [Iberian], and APP E693G [Arctic] mutations), human hippocampal samples, and human cultured cell lines. Their results revealed that running-induced miR-132 upregulation in the hippocampal neurogenic niche becomes compromised with pathology progression, independently of gender, and that these alterations are paralleled by decreased neurogenic potential. Their data also demonstrate that treatment of human neuronal precursor cells with oligomeric Aβ reduces proliferation and miR-132 expression. At the transcriptomic level, the authors demonstrate a miR132-specific molecular signature consisting of DOCK1, EPHB3, BTG2, CAMK1, and RAC1, all of which have reported roles in neuronal differentiation and function. Interestingly, miR-132 knockdown also inhibited the running-induced increase of Bdnf, a key neurotrophic factor contributing to neurogenic potential. Of note, miR-132 overexpression in wild-type mice produced worse performance in the AHN-specific pattern separation task, suggesting that miR-132 expression should be maintained within a certain range to ensure proper learning and memory function. The data presented in this important article support the view that miR-132 acts as a proneurogenic signal transducer contributing to the molecular basis of memory formation. Within this scenario, AD pathology leads to miR-132 deficiency and ultimately compromises AHN. These results