Oligomeric β-amyloid (Aβ) has recently been linked to synaptic plasticity deficits, which play a major role in progressive cognitive decline in Alzheimer's disease (AD). Here we present evidence that chronic oral administration of carvedilol, a nonselective β-adrenergic receptor blocker, significantly attenuates brain oligomeric β-amyloid content and cognitive deterioration in 2 independent AD mouse models. We found that carvedilol treatment significantly improved neuronal transmission, and that this improvement was associated with the maintenance of number of the less stable “learning” thin spines in the brains of AD mice. Our novel observation that carvedilol interferes with the neuropathologic, biochemical, and electrophysiological mechanisms underlying cognitive deterioration in AD supports the potential development of carvedilol as a treatment for AD.
Alzheimer's disease (AD) is a devastating neurological disorder that imposes a tremendous health burden on society. Currently available palliative medications have not demonstrated significant beneficial effects in AD (Lyketsos et al., 2004) and treat symptoms only.
Growing evidence suggests that cognitive deterioration in AD is directly linked to the accumulation of extracellular soluble oligomeric β-amyloid (Aβ) species, rather than amyloid plaque deposition in the brain (Cleary et al., 2005, Gylys et al., 2003, Klyubin et al., 2005, Kotilinek et al., 2002, Lambert et al., 1998, Lesne et al., 2006 and Shankar et al., 2008). Oligomeric Aβ induces synapse degeneration and synaptic plasticity disruption, which contribute to mechanisms underlying the onset and progression of dementia in AD (Coleman et al., 2004, Jacobsen et al., 2006, Lacor et al., 2004, Scheff and Price, 2003, Selkoe, 2002, Shankar et al., 2007, Shankar et al., 2008, Terry et al., 1991 and Walsh et al., 2002). Thus, interference with oligomeric Aβ formation presents a viable preventative and/or therapeutic strategy for AD dementia (Klein, 2002, McLaurin et al., 2006, Seabrook et al., 2007 and Zhao et al., 2009).
Carvedilol is a nonselective β-adrenergic receptor blocker, widely prescribed for treating congestive heart failure and hypertension (Packer et al., 1996). Previous structural analysis suggested that carvedilol possesses a specific 3-dimensional pharmacophore conformation, associated with the ability to bind Aβ and prevent Aβ from forming oligomeric fibrils (Howlett et al., 1999). A recent study suggested that use of carvedilol is associated with cognitive benefits in AD patients (Rosenberg et al., 2008). In the present study, we explored the potential beneficial role of carvedilol in AD neuropathology and cognitive deterioration in mouse models of AD, in addition to the potential mechanism associated with its beneficial effect.
