Overexpressing a single anti-apoptotic protein on top of an already triple-transgenic model of Alzheimer disease (AD) rescues amyloid and tau pathology in the resulting quadruple-engineered mice. Published in the March 19 Journal of Neuroscience, the finding supports the idea that activation of apoptosis in general, and caspases in particular, may participate in Alzheimer pathology.

Researchers led by Troy Rohn at Boise State University, Idaho, and Elizabeth Head at the University of California, Irvine, crossed 3xTG-AD mice (with human amyloid precursor protein, presenilin, and tau genes) developed at Frank LaFerla’s lab (see Oddo et al., 2003) with mice that overexpress human Bcl-2 in CNS neurons. Bcl-2 is a mitochondria-based anti-apoptotic warrior that prevents the activation of caspase enzymes, key players in the programmed cell death cascade. There is no consensus on the importance of apoptosis in AD pathogenesis, but the process is activated in many diseased neurons in AD. Caspases are known to cleave Aβ and tau under certain conditions.

Rohn and colleagues found that overexpression of Bcl-2 prevented cellular redistribution and activation of caspase-9 and activation of one of its targets, caspase-3. Caspase-9 is a well-known tau caspase, and it and caspase-3 are also potential cleavage enzymes for the APP intracellular domain (AICD). In fact, eliminating the AICD caspase site rescues pathology in APP-transgenic mice (see ARF related news story).

How does reduction of caspase-9 activity affect pathology in these 3xTG animals? The researchers found that caspase cleavage of tau, which in triple transgenics is seen in hippocampal apical dendrites as early as six months of age, was both delayed and significantly reduced. This appears to affect the turnover of tau, because the authors found that total tau increased by about 2.5-fold in 12- to 18-month-old Bcl-2/triple crosses. Surprisingly, neurofibrillary tangles could barely be detected in these animals, suggesting that caspase cleavage may be crucial for those inclusions to form.

The researchers found similar changes in APP processing in 12- to 18- month-old crosses. As if protected by Bcl-2 overexpression, APP accumulated intracellularly, but in keeping with reduced turnover, levels of soluble and insoluble Aβ were lower than in the triple transgenics. There was also no evidence of extracellular plaques. “Overall, these results suggest a significant role for caspase-like proteolytic activity in the processing of APP and production of Aβ,” write the authors. Studying two mice that matured to 24 months, the researchers also found that Bcl-2 overexpression improved their cognition.

How representative this heavily engineered model is to human physiology is unclear. But there are other indications that Bcl-2 may be protective in AD. Researchers led by Giulio Taglialatela at the University of South Florida, Tampa, reported last year that Bcl-2 is upregulated in an APP/PS1 mouse model that has limited Aβ toxicity (see Karlnoski et al., 2007), while Carl Cotman and colleagues at the University of California, Irvine, showed that Bcl-2 is upregulated in AD brain (see Su et al., 1997). Rohn and colleagues conclude that “thus, therapeutics designed to stimulate the activity of Bcl-2 within neurons of the AD brain may provide an effective means for stopping the progression of this disease.” In an e-mail to ARF, Rohn wrote that Bcl-2 inhibitors have been designed as anti-cancer drugs (some cancer cells are notoriously resistant to apoptosis), but he knows of no molecules that might activate Bcl-2. He suggested that one of the problems with this approach, or with inhibiting caspases, will be selectivity.—Tom Fagan


  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.


    . 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.

  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.


    . 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.

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News Citations

  1. Paper Alert: Pathology Reversed by Abolishing APP Caspase Site

Paper Citations

  1. . Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.
  2. . Up-regulation of Bcl-2 in APP transgenic mice is associated with neuroprotection. Neurobiol Dis. 2007 Jan;25(1):179-88. PubMed.
  3. . Bax protein expression is increased in Alzheimer's brain: correlations with DNA damage, Bcl-2 expression, and brain pathology. J Neuropathol Exp Neurol. 1997 Jan;56(1):86-93. PubMed.

Further Reading


  1. . Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer's disease. Exp Neurol. 2005 Oct;195(2):484-96. PubMed.
  2. . Role of calpain and caspase in beta-amyloid-induced cell death in rat primary septal cultured neurons. Neuropharmacology. 2008 Mar;54(4):721-33. PubMed.
  3. . Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease. Neurobiol Dis. 2008 Mar;29(3):456-64. PubMed.
  4. . No difference in expression of apoptosis-related proteins and apoptotic morphology in control, pathologically aged and Alzheimer's disease cases. Neurobiol Dis. 2006 May;22(2):323-33. PubMed.

Primary Papers

  1. . 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.