20 March 2008. 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.
Rohn TT, Vyas V, Hernandez-Estrada T, Nichol KE, Christie L-A, Head E. Lack of pathology in a triple transgenic mouse model of Alzheimer’s disease after overexpression of that anti-apoptotic protein Bcl-2. J. Neurosci. 2008 Mar 19;28:3051-3059. Abstract