Bim Is Elevated in Alzheimer's Disease Neurons and Is Required for β-Amyloid-Induced Neuronal Apoptosis

Abstract

The molecules that mediate neuron death in Alzheimer's disease (AD) are largely unknown. We report that ␤-amyloid (A␤), a deathpromoting peptide implicated in the pathophysiology of AD, induces the proapoptotic protein Bcl-2 interacting mediator of cell death (Bim) in cultured hippocampal and cortical neurons. We further find that Bim is an essential mediator of A␤-induced neurotoxicity. Our examination of postmortem AD human brains additionally reveals upregulation of Bim in vulnerable entorhinal cortical neurons, but not in cerebellum, a region usually unaffected by AD. Accumulating evidence links inappropriate induction/activation of cell cycle-related proteins to AD, but their roles in the disease have been unclear. We find that the cell cycle molecule cyclin-dependent kinase 4 (cdk4) and its downstream effector B-myb, are required for A␤-dependent Bim induction and death in cultured neurons. Moreover, neurons that overexpress Bim in AD brains also show elevated levels of the cell cycle-related proteins cdk4 and phospho-Rb. Our observations indicate that Bim is a proapoptotic effector of A␤ and of dysregulated cell cycle proteins in AD and identify both Bim and cell cycle elements as potential therapeutic targets.

Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-β and prion peptides

“…This is also confirmed by studies in human AD brains that showed considerably increased Cdk4 levels, whereas cyclin D1 only varies in a low percentage. 23,24 However, the observations in AD patients, as well as our own data, contrast with the results obtained in mouse models of AD 46 and of other neurodegenerative conditions 18,47 where increased levels of cyclin D1 were found. This difference between AD animal models and patients is further reinforced if we consider that the majority of the mouse models for this disease, although exhibiting one or even more of the neuropathological features of AD, fail to exhibit neuronal death.…”

“…Since Cdk4 is directly involved in the first steps of cell cycle reactivation and increased levels of this kinase have been shown to occur in the brains of AD patients, 23,24 we started by assessing Cdk4 levels by Western Blot. As can be seen in Figures 1A and 2, Aβ and PrP 106-126 , at 24 h of incubation, caused a significant increase (p < 0.05) in the levels of this kinase, by 13.3 ± 3.3% and 13.2 ± 2.8%, respectively.…”

“…23,35 Interestingly, in several pathologies in which ectopic cell cycle events have been described, Cdk5 overactivation also occurs. 6,9,10,25,37 However, little is known about the connection between both events.…”

“…[20][21][22] Therefore we analyzed various proteins, associated with different phases of the cell cycle, in cultured cortical neurons untreated or treated with the synthetic peptides Aβ or PrP . The events related with the G 1 /S transition were evaluated by measuring the levels and subcellular localization of Cdk4, Cyclin D1 and pRb, 23,24 whereas to determine if the cell cycle re-entering neurons pass the S phase and overcome the G 2 /M checkpoint we assessed the levels…”

CITED2 Signals through Peroxisome Proliferator-Activated Receptor-γ to Regulate Death of Cortical Neurons after DNA Damage

“…We previously showed that cyclin D1-associated Cdks (Cdk4/6) are aberrantly activated in neurons after DNA damage (Park et al, 1998) and various different in vitro neuronal death paradigms (Park et al, 1996(Park et al, , 1997bGiovanni et al, 1999;Padmanabhan et al, 1999;Rideout et al, 2003). This evidence also extends to in vivo injury and neurodegenerative contexts including after stroke/ischemia (Osuga et al, 2000), Alzheimer's disease (McShea et al, 1997;Biswas et al, 2007), and amyotrophic lateral sclerosis (Nguyen et al, 2003). We and others have shown that Cdk4/6 activity is essential to signal death in many paradigms of neuronal apoptosis, including after DNA damage in vitro (Park et al, 1998;Morris et al, 2001;Zhang et al, 2006) and stroke in vivo (Rashidian et al, 2005).…”