Amyloid β Peptide of Alzheimer’s Disease Downregulates Bcl-2 and Upregulates Bax Expression in Human Neurons

Abstract

Neuronal apoptosis is a suspected cause of neurodegeneration in Alzheimer's disease (AD). Increased levels of amyloid beta peptide (Abeta) induce neuronal apoptosis in vitro and in vivo. The underlying molecular mechanism of Abeta neurotoxicity is not clear. The normal concentration of Abeta in cerebrospinal fluid is 4 nM. We treated human neuron primary cultures with 100 nM amyloid beta peptides Abeta(1-40) and Abeta(1-42) and the control reverse peptide Abeta(40-1). We find that although little neuronal apoptosis is induced by either peptide after 3 d of treatment, Abeta(1-42) provokes a rapid and sustained downregulation of a key anti-apoptotic protein, bcl-2, whereas it increases levels of bax, a protein known to promote cell death. In contrast, the Abeta(1-40) downregulation of bcl-2 is gradual, although the levels are equivalent to those of Abeta(1-42)-treated neurons by 72 hr of treatment. Abeta(1-40) does not upregulate bax levels. The control, reverse peptide Abeta(40-1), does not affect either bcl-2 or bax protein levels. In addition, we found that the Abeta(1-40)- and Abeta(1-42)- but not Abeta(40-1)-treated neurons had increased vulnerability to low levels of oxidative stress. Therefore, we propose that although high physiological amounts of Abeta are not sufficient to induce apoptosis, Abeta depletes the neurons of one of its anti-apoptotic mechanisms. We hypothesize that increased Abeta in individuals renders the neurons vulnerable to age-dependent stress and neurodegeneration.

Mitochondrial DNA Damage as a Mechanism of Cell Loss in Alzheimer's Disease

“…The accumulation of A␤-amyloid in brains with AD may be important in this regard because increased levels of Bax and p53 immunoreactivity have been localized within and around A␤-amyloid deposits in senile plaques (de la Monte et al, , 1998Su et al, 1997;Tortosa et al, 1998). Experimentally, A␤-amyloid has been shown to be neurotoxic or to induce proapoptosis and inhibit cell survival gene expression (Davis et al, 1999;Forloni et al, 1996;Giambarella et al, 1997;Gunn-Moore and Tavare, 1998;Ivins et al, 1999;Paradis et al, 1996;Prehn et al, 1996;Sayre et al, 1997a;Yamatsuji et al, 1996) and activate oxidative stress-related genes (Pappolla et al, 1998). Moreover, A␤-amyloid-induced cellular degeneration can be rescued or prevented by treatment with antioxidant or free-radical scavenger agents (Prehn et al, 1996).…”

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

“…29 Moreover, evidence suggesting a cause-and-effect relation between increases in Bax expression and ischemia-associated neuronal cell death has come from experiments using baxÀ/À mice generated by Korsmeyer et al 30 Elevations in Bax protein and mRNA levels were described in neurons in vivo after excitotoxic lesion with the N-methyl-D-aspartate receptor agonist, quinolinic acid, 31 as well as after systemic administration of kainic acid. 32 Of potential relevance to neurodegenerative diseases, amyloidbeta peptide was reported to upregulate Bax and downregulate Bcl-2 in cultured human neurons, 33 and systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to cause increases in Bax mRNA and protein in the substantia nigra. 34 In addition to neuronal cell death associated with ischemia and excitotoxic neurotransmitters, Bax protein levels are markedly increased in sensory and motor neurons following sciatic nerve transection, often in association with increases in Jun protein production.…”

Distinct susceptibility of developing neurons to death following Bax overexpression in the chicken embryo

“…2 Other studies pointed out that the expression of Bax increases during PCD, as well as under pathological conditions. 3,6,[10][11][12][13] In the present studies, we initially examined the effects of Bax overexpression on several different neuronal populations that undergo normal PCD. These include the early phase of developing retinal PCD which appears to be induced by death signaling through NGF and TGF-b, 30,31 as well as the common type of neuronal PCD that occurs in developing sensory and MNs of the spinal cord after forming synaptic connections with targets.…”

“…3,6,10 The balance can be changed in favor of proapoptosis in several pathological conditions which cause neuronal damage. [11][12][13] It has been previously reported that overexpression of Bax induces death of cultured neurons in the absence of obvious apoptotic stimuli. 3 Therefore, the relative levels of Bax expression may in itself be important for regulating cell death in developing neuron even in the absence of extracellular proapoptotic signals.…”