Birthing newborn neurons in the adult brain is a complex process with lots of moving parts. Papers in the July 30 eNeuro illuminate the need for two key proteins, both well known for their role in Alzheimer’s disease. Rudolph Tanzi and Se Hoon Choi at Massachusetts General Hospital, Boston, report that lack of BACE1 permits over-proliferation of neural progenitors, but prevents their differentiation into mature neurons. The results imply that BACE1 inhibition, if too powerful, could reduce the number of mature neurons in the hippocampus. Writing in the second paper, Steven Kernie and colleagues at Columbia University, New York, posit that ApoE4 stunts the maturation of newborn neurons in adult mice, thinning their dendritic arbors. Together, these two papers suggest that, at least in the case of adult neurogenesis, BACE inhibition might have a similar effect to ApoE4.
- Proteins involved in neurodegeneration linked to adult neurogenesis.
- BACE1 promotes maturation of progenitor cells in the mouse hippocampus.
- ApoE3, but not E4, supports the growth and branching of dendrites in new neurons.
“These findings point toward the need to understand the neurodevelopmental roles of proteins involved in neurodegeneration while designing potential treatments for AD,” wrote Beate Winner, Friedrich-Alexander-University of Erlangen-Nürnberg, Germany, to Alzforum. Winner was not involved in either study.
Forever Young. Without BACE (right), more newborn neurons proliferate than in mice with BACE (left), but fewer develop into mature neurons. [Courtesy of Emma Brand/Massachusetts General Hospital.]
No BACE1, No New Neurons
BACE1 is best known for making the first enzymatic cut in the Ab precursor protein (APP) as it is processed to release Ab. More recently, the enzyme was recognized for regulating developmental neurogenesis (Hu et al., 2013). Young BACE1 knockout mice had fewer newborn neurons in their hippocampi. Tanzi, Choi, and colleagues wondered if knocking out the enzyme had a similar effect on adult neurogenesis as well.
To find out, co-first authors Zena Chatila, Eunhee Kim, and Clara Berlé used heterozygous BACE+/- mice from the lab of Mark Albers, Massachusetts General Hospital, and bred them to have either two, one, or no copies of the BACE1 enzyme. After aging them to two months, they gave each a single intraperitoneal injection of bromodeoxyuridine (BrdU), a stand-in for thymidine in newly formed DNA, to label newborn neurons. They euthanized half the mice one day after injection and sectioned their brains to see if BACE1 affected proliferation of progenitor cells. The remaining mice were aged for four weeks to give newborn neurons time to mature and integrate into the surrounding circuitry. The researchers then looked for BACE1 effects on survival and differentiation of nascent neurons.
After one day, the number of proliferating cells in the dentate gyri of BACE1 knockout mice almost doubled that in the BACE1 hetero- or homozygotes. However, four weeks later, relatively few of these young cells had matured. In the knockouts, up to 40 percent fewer of the BrdU+ cells expressed NeuN, a marker of neurons, as compared to cells in control mice. Most of these didn’t express doublecortin, olig2, or GFAP either; markers of immature neurons, oligodendrocytes, and astrocytes, respectively. Instead, this pool of neural progenitor cells appeared to stall in an undifferentiated state. There were no differences among BACE1 homo- and heterozygous mice, suggesting proliferation and maturation proceed normally with only partial knockout of the enzyme.
Based on these results, the authors propose that in people with AD, complete inhibition of BACE1 could lead to a pool of cells that get stuck in a stem-cell-like state. “While full BACE1 inhibition is not a goal for patients, 50 percent or slightly more appears fully acceptable,” wrote Stefan Lichtenthaler, German Center for Neurodegenerative Diseases, Munich (see full comment below). “Importantly, for prevention trials it is likely that even less than 50 percent BACE1 inhibition would be sufficient, which should prevent basically all potential side effects.” He suggested repeating the study with a BACE1 inhibitor to determine how much inhibition allows normal neurogenesis.
Carmen Birchmeier, Max Delbrück Center for Molecular Medicine, Berlin, pointed out that it is not yet clear how detrimental it would be if it adult neurogenesis was curtailed. BACE1 cleaves many substrates and BACE KOs have many other troubling phenotypes, including reduced muscle spindle formation, uncoordinated movement, and spontaneous seizures “Independently of this [study], the suggestion not to fully inhibit BACE1 but rather reduce its activity is good, just to be on the safe side.”
ApoE4 Stops Neurons Branching Out
Kernie and colleagues similarly wondered if ApoE influenced adult neurogenesis. They previously reported that the murine version of the protein puts the brakes on progenitor proliferation and prevents stores of neural stem cells from becoming depleted too early (Yang et al., 2011). Does it affect the ongoing development of these cells, too?
First author Yacine Tensaouti and colleagues compared adult wild-type mice with ApoE knockouts. They also compared ApoE3 targeted replacement mice to their ApoE4 counterparts. In these animals, human isoforms replace the murine gene. By injecting the dentate gyri of six-week-old animals with a GFP-encoding retrovirus that only incorporates into dividing cells, they specifically labeled the newborn cells in the hippocampi. Four weeks later, they examined them.
Compared with the adult-born neurons in wild-type mice and in animals with human ApoE3, those in both the ApoE knockout and in ApoE4 targeted replacement mice had shorter, sparser dendrites with fewer spines and branch points (see image at right). In all mice, astrocytes that expressed ApoE wrapped around these new dendrites. The results hint that in astrocytes murine ApoE and human ApoE3 give dendrites a maturational boost, while ApoE4 does not.
“We know that ongoing neurogenesis is important for keeping a healthy, dynamically functioning hippocampus,” Kernie told Alzforum. “What this study shows is that if mice have ApoE4, their ability to do that is not as robust as in mice that express ApoE3. That probably impairs the ability of the hippocampus to develop normally and to respond to injury.” However, it is still unclear how neurogenesis influences AD in people, he noted.
Guojun Bu, Mayo Clinic, Jacksonville, Florida, who was not involved in the study, thought it was well-executed. He still thinks the main reason for the increased AD risk brought by ApoE4 is that the protein drives earlier and more abundant amyloid pathology. However, there is increasing evidence that ApoE4 also has a loss of function compared to E3. “In a model such as this, where there’s no AD-related pathology, a deficiency of ApoE4 supports this notion.” He cautioned that the authors did not test whether the differences they observed in neurogenesis and morphology had any impact on function.—Gwyneth Dickey Zakaib
- Hu X, He W, Luo X, Tsubota KE, Yan R. BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep. 2013 Jul 11;4(1):40-9. PubMed.
- Yang CP, Gilley JA, Zhang G, Kernie SG. ApoE is required for maintenance of the dentate gyrus neural progenitor pool. Development. 2011 Oct;138(20):4351-62. PubMed.
- Koutseff A, Mittelhaeuser C, Essabri K, Auwerx J, Meziane H. Impact of the apolipoprotein E polymorphism, age and sex on neurogenesis in mice: Pathophysiological relevance for Alzheimer's disease?. Brain Res. 2013 Oct 16; PubMed.
- Horgusluoglu E, Nudelman K, Nho K, Saykin AJ. Adult neurogenesis and neurodegenerative diseases: A systems biology perspective. Am J Med Genet B Neuropsychiatr Genet. 2017 Jan;174(1):93-112. Epub 2016 Feb 16 PubMed.
- Chatila ZK, Kim E, Berlé C, Bylykbashi E, Rompala A, Oram MK, Gupta D, Kwak SS, Kim YH, Kim DY, Choi SH, Tanzi RE. BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice. eNeuro. 2018 Jul-Aug;5(4) Epub 2018 Aug 3 PubMed.
- Tensaouti Y, Stephanz EP, Yu TS, Kernie SG. ApoE Regulates the Development of Adult Newborn Hippocampal Neurons. eNeuro. 2018 Jul-Aug;5(4) Epub 2018 Aug 2 PubMed.