The hopes for treating Alzheimer disease by inhibiting the amyloid-producing enzyme β-secretase (BACE) rest largely on results obtained in mice, particularly the finding that mice lacking the BACE1 gene lose essentially all their amyloid-β peptide production and become resistant to developing AD. As a bonus, the loss of BACE1 appeared to cause no gross physical or physiological abnormalities, raising the prospect that BACE inhibitors might come with few side effects.
However, mice sans BACE1 are not totally unscathed. Detailed studies on the knockout mice, including work from Fiona Laird and Philip Wong of the Johns Hopkins University in Baltimore, Maryland, revealed that BACE knockouts had problems with synaptic function and plasticity, and behavioral problems as well (see ARF related news story; Laird et al., 2005; and Harrison et al., 2003). BACE knockout mice have a surfeit of myelination in the peripheral nervous system (see ARF related news story), which may be related to a lack of cleavage of the neurotrophic factor neuregulin (NRG). More recent work, also from the Wong lab, revealed that the BACE1 knockouts displayed several behaviors associated with schizophrenia in people (see ARF related news story).
A new report extends the synaptic story, showing that BACE1 knockout mice lose the capacity for long-term potentiation in mossy fiber terminals, the site of the highest BACE protein levels in the mouse hippocampus. The results, from Hey-Kyoung Lee and colleagues at the University of Maryland at College Park, along with Laird and Wong, augment the idea that wholesale inhibition of BACE may be less benign than many had hoped. The work appears in a Brief Communication in the August 27 Journal of Neuroscience.
Previous work on the synaptic effects of BACE deficiency in mice had focused on changes in the CA1 region of the hippocampus, but the BACE1 protein is most abundant in the mossy fibers that synapse onto CA3 neurons. Looking specifically at these neurons, first author Hui Wang and colleagues measured an increase in paired pulse facilitation in hippocampal slices from the knockouts, which suggests a reduction in presynaptic neurotransmitter release. In addition, they found that activity-dependent long-term potentiation at mossy fiber synapses was abolished in the BACE knockouts. The effects on LTP also seemed to stem from presynaptic problems, because downstream calcium-initiated signaling appeared to be intact in BACE1 knockouts. Indeed, the induction of LTP could be rescued by increasing extracellular calcium concentrations.
“We found that BACE knockouts display severe deficits in presynaptic function at mossy fiber synapses in CA3,” the authors conclude. “These results suggest that BACE1 function is critical for normal synaptic transmission and plasticity, especially activity-dependent potentiation, at these synapses.” Not clear, they say in the paper, is whether this involves the loss of amyloid precursor protein processing, or if the effects might involve other substrates.
“Our results indicate that a complete inhibition of BACE1 activity is deleterious for neuronal function,” the authors write. However, they suggest that enhancing presynaptic calcium might be a way to alleviate synaptic effects and behavioral phenotypes associated with BACE1 inhibition.
One prominent BACE substrate is neuregulin (NRG), a membrane-tethered neurotrophic factor that signals via ErbB family receptors. Modulation of NRG/ErbB signaling at synapses is one way that BACE1 activity might affect synaptic function, the authors write. The BACE-NRG connection comes up in another context, too, which is the regulation of myelination of axons. Neuregulin acts in the peripheral nervous system to control the development of Schwann cells and stimulate them to wrap axons with a myelin sheath. Indeed, a failure of NRG cleavage in BACE knockout mice explains their phenotype of loss of peripheral myelin (Willem et al., 2006).
However, the potential demyelinating effects of NRG inhibition may not translate into the CNS, according to new data from Markus Schwab and Klaus Armin Nave at the Max Planck Institute of Experimental Medicine in Goettingen, Germany. In their paper, published in the August 28 issue of Neuron, the researchers led by first authors Bastian Brinkmann and Amit Agarwal show that in brain-specific neuregulin or ErbB knockout mice, myelination proceeds normally for CNS neurons. The results reveal a surprising divergence of function for the NRG1/ErbB pathways between Schwann cells in the periphery and oligodendrocytes in the CNS. BACE knockout mice have been reported to have deficits in CNS myelination (Hu et al., 2006), but the current work suggests that may not be explained by a defect in neuregulin processing. It appears that, just as in the case of the synaptic effects of BACE inhibition, the responsible targets for myelination are still at large.—Pat McCaffrey
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- Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci. 2005 Dec 14;25(50):11693-709. PubMed.
- Harrison SM, Harper AJ, Hawkins J, Duddy G, Grau E, Pugh PL, Winter PH, Shilliam CS, Hughes ZA, Dawson LA, Gonzalez MI, Upton N, Pangalos MN, Dingwall C. BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci. 2003 Nov;24(3):646-55. PubMed.
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- Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006 Dec;9(12):1520-5. Epub 2006 Nov 12 PubMed.
- Wang H, Song L, Laird F, Wong PC, Lee HK. BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus. J Neurosci. 2008 Aug 27;28(35):8677-81. PubMed.
- Brinkmann BG, Agarwal A, Sereda MW, Garratt AN, Müller T, Wende H, Stassart RM, Nawaz S, Humml C, Velanac V, Radyushkin K, Goebbels S, Fischer TM, Franklin RJ, Lai C, Ehrenreich H, Birchmeier C, Schwab MH, Nave KA. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron. 2008 Aug 28;59(4):581-95. PubMed.