. Lack of pathology in a triple transgenic mouse model of Alzheimer's disease after overexpression of the anti-apoptotic protein Bcl-2. J Neurosci. 2008 Mar 19;28(12):3051-9. PubMed.

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  1. In this elegant paper, Rohn and colleagues show that overexpressing the anti-apoptotic protein Bcl-2 prevents the development of Alzheimer-like pathology and cognitive deficits in the 3xTg mouse model of AD. These data strengthen the growing body of evidence that caspase cleavage of tau seeds fibrillization and is necessary for NFT formation. Our ongoing studies in another mouse model of tauopathy (rTg4510) using in vivo multiphoton imaging also show an association between caspase activation and neurofibrillary tangle pathology (Spires-Jones et al., 2008).

    Because the 3xTg model does not undergo neuronal loss, this paper does not contribute to the discussion of whether apoptosis is involved in cell death in AD, but the recovery of cognitive function with Bcl-2 overexpression raises the very interesting possibility that anti-apoptotic factors can improve cognition without preventing neuronal loss. Both plaques and tangles are associated with synapse loss and abnormalities in neurite architecture, so preventing the formation of these pathological hallmarks may well prevent loss of connectivity that leads to cognitive decline. It will be very interesting to see data about whether synapse loss is prevented with Bcl-2 expression.

    References:

    . In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons. J Neurosci. 2008 Jan 23;28(4):862-7. PubMed.

    View all comments by Tara Spires-Jones
  2. This exciting report led by Troy Rohn at Boise State University and Elizabeth Head at UC Irvine quite convincingly shows a remarkable effect of Bcl-2 overexpression in curbing Aβ and tau pathology in the brain of 3xTg-AD mice. The authors elegantly show that this action of Bcl-2 involves reducing caspase-9 activation, but is independent of prevention of neuronal death which, as in many other AD transgenic mouse models, is not present in 3xTg-AD mice to any significant degree. This is an important in vivo insight into the still poorly characterized role of Bcl-2 in cell signaling beyond its regulation of apoptosis.

    In collaboration with David Morgan at the University of South Florida at Tampa, we reported that endogenous Bcl-2 is upregulated in the CNS of APP/PS1 doubly transgenic mice and that such upregulation may be neuroprotective (Karlnoski et al., 2007). Rohn and Head used an anti-Bcl-2 antibody that detects the exogenously expressed human Bcl-2 but does not recognize mouse Bcl-2. Given the lack of neuronal death in the 3xTg-AD mice, it would be interesting in the future to determine whether this mouse model, too, displays upregulated endogenous Bcl-2 in response to the amyloid and tau pathology. Be that as it may, Rohn and Head clearly show that the excess Bcl-2 ameliorates neuropathology and cognition in 3xTg-AD mice and propose that Bcl-2 may act by alleviating synaptic dysfunction. This is a very interesting idea that, considering the reported growing role of synaptic (dys)function in the etiology of symptomatic AD, well deserves further consideration. We have recently reported that calcineurin, a phosphatase abundant in CNS neurons and negatively involved in the modulation of synaptic plasticity and memory function, is upregulated in the CNS of singly APP transgenic mice (Tg2576) and that acute pharmacological normalization of calcineurin reverses the deficits in the fear conditioning memory task that are normally found in these mice (Dineley et al., 2007). Interestingly, in neuronal tissue, Bcl-2 has been reported to bind to CaN and sequester it (Erin et al., 2003). On this account, whether overexpressed Bcl-2 may contrast calcineurin activity in the brain of 3xTg-AD mice and so alleviate synaptic dysfunction would be a formidable question to ask.

    In summary, I believe that this report may reshape our way of looking at and thinking of Bcl-2 in the context of AD-associated neuropathology. I also think that this report might have opened an interesting can of worms. And these are good worms, the kind you would like to have when going fishing for a big catch.

    References:

    . Up-regulation of Bcl-2 in APP transgenic mice is associated with neuroprotection. Neurobiol Dis. 2007 Jan;25(1):179-88. PubMed.

    . Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem. 2007 Sep;88(2):217-24. PubMed.

    . Calcium-dependent interaction of calcineurin with Bcl-2 in neuronal tissue. Neuroscience. 2003;117(3):541-55. PubMed.

    View all comments by Giulio Taglialatela