Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, Ávila J, Llorens-Martín M. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease. Nat Med. 2019 Apr;25(4):554-560. Epub 2019 Mar 25 PubMed.

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  1. This is a rigorous and well-controlled study addressing the controversial issue of adult hippocampal neurogenesis in aging humans. The data demonstrating a relationship between parameters of tissue processing, particularly postmortem interval and duration of fixation, and detection of doublecortin (DCX)-positive immature neurons in the dentate gyrus is clear and may underlie some of the disparate findings on adult human neurogenesis from different groups.

    The results are consistent with our recently reported observation of accelerated differentiation and depletion of neural progenitors at an early stage in induced pluripotent stem cell models of sporadic AD and APOE4 (Meyer et al., 2019). Our findings predict that the neural progenitor pool would be depleted in individuals predisposed to AD, and during aging might reach a tipping point after which neurogenesis declines. The Moreno-Jimenez report did not analyze the neural progenitor population in aging control or AD brains, making it difficult to know if loss of neural progenitors is a cause of the reduced neurogenesis they observe in AD dentate gyrus. They did, however, investigate if altered maturation of immature neurons might be involved and concluded that there was some effect on maturation based on an association between maturation-related markers and the progression of pathology as determined by Braak scores. However, examination of the data (Fig. 4 c-i) suggests that for many of the maturation markers, there is a decline between control and Braak 1, with little difference between Braak 1 and Braak 6 (PSA-NCAM, Prox1, NeuN, and calbindin). This raises the possibility that the major change in neurogenesis occurs very early in the disease. To resolve this issue, it will be important for subsequent studies to analyze the state of the neural progenitor population at different stages of AD, beginning with cases of mild cognitive impairment.

    References:

    Meyer K, Feldman HM, Lu T, Drake D, Lim ET, Ling KH, Bishop NA, Pan Y, Seo J, Lin YT, Su SC, Church GM, Tsai LH, Yankner BA. REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease. Cell Rep. 2019 Jan 29;26(5):1112-1127.e9. PubMed.

    View all comments by Bruce Yankner

  2. Reading this paper reminded me of some data that we published a few years ago on a brain-penetrant retro-inverso peptide inhibitor that blocks Aβ oligomer and fibril formation (see Parthsarathy et al., 2013). One of the most striking findings arising from the repeated injection of APP/PS1 transgenic mice with this peptide inhibitor was the dramatic increase (by 210 percent, p=0.0001) in the mean number of young doublecortin-expressing neurons in the dentate region of the hippocampus, compared to control/saline treated animals. This suggested to us at the time that Aβ oligomers could have a major negative impact on brain neurogenesis. Perhaps this is an aspect of amyloid therapy that has been largely overlooked and deserves further investigation.

    References:

    Parthsarathy V, McClean PL, Hölscher C, Taylor M, Tinker C, Jones G, Kolosov O, Salvati E, Gregori M, Masserini M, Allsop D. A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease. PLoS One. 2013;8(1):e54769. PubMed.

    View all comments by David Allsop

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  1. Neurogenesis Tapers In Older Brains, But Plummets in Alzheimer’s