Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

Abstract

More than a century has elapsed since the description of Alois Alzheimer's patient Auguste D. Yet, the well-documented generation of beta-amyloid aggregates and neurofibrillary tangles that define Alzheimer's disease is believed to represent only a portion of the cellular processes that can determine the course of Alzheimer's disease. Understanding of the complex nature of this disorder has evolved with an increased appreciation for pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Recent work has identified novel pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and the formation of neurofibrillary tangles through their downstream substrates that include glycogen synthase kinase-3beta, Bad, and Bcl-xL. Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation for the processing of amyloid precursor protein, tau protein cleavage, and presenilin disposal. New therapeutic avenues that are just open to exploration, such as with nicotinamide adenine dinucleotide modulation, cell cycle modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat Alzheimer's disease.

Fig. 1

Representative clinical pathology of Alzheimer's disease. Microscopic evaluation of the cerebral cortex with a silver stain in a patient with Alzheimer's disease demonstrating “senile plaques” with neuronal degeneration. Image supplied by Daniel P. Perl, M.D., of Mount Sinai School of Medicine. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Images of neurofibrillary tangles in Alzheimer's disease. In this section of the cerebral cortex in a patient with Alzheimer's disease, several neurofibrillary tangles can be visualized with a silver stain. Image supplied by Daniel P. Perl, M.D., of Mount Sinai School of Medicine. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Over-expression of Wnt-1 prevents β-amyloid (Aβ)-induced DNA fragmentation and membrane phosphatidylserine (PS) exposure in human neuroblastoma SH-SY5Y cells. Representative images of SH-SY5Y cells illustrate DNA fragmentation with terminal deoxynucleotidyl transferase nick end labeling (TUNEL) and phosphatidylserine (PS) exposure with annexin V phycoerythrin labeling in SH-SY5Y cells 24 h after administration of Aβ (20 μM). Aβ yielded significant DNA fragmentation and membrane PS exposure when compared to control untreated cultures. In contrast, overexpression of Wnt-1 results in a significant reduction in DNA fragmentation and PS exposure.

Fig. 4

Oxidative stress in primary hippocampal neurons leads to microglia activation and proliferation. Pure microglial cultures were treated for 3 h with media from rat hippocampal neuronal cultures conditioned with 24 h of oxidative stress (nitric oxide, 300 μM). Representative images illustrate the significant expression of proliferating cell nuclear antigen (PCNA) (microglial activation) or the uptake of bromodeoxyuridine (BrdU) (microglial proliferation) in microglia treated with media from neurons exposed to oxidative stress when compared to control cultures. In all cases, control = treated with media from neurons not exposed to oxidative stress.

Fig. 5

Wnt and Akt signaling pathways in Alzheimer's disease. The common downstream target of Wnt and Akt, glycogen synthase kinase-3 β (GSK-3β), phosphorylates tau protein facilitating the formation of neurofibrillary tangles. GSK-3β also phosphorylates (P) β-catenin leading to its degradation and subsequent induction of apoptosis. GSK-3β may also influence the amyloid precursor protein (APP) processing resulting in an increase in the production of Aβ, which conversely increases the activity of GSK-3β. Akt inhibits GSK-3β through phosphorylation and also phosphorylates tau protein at the site of Ser²¹⁴ to prevent formation of neurofibrillary tangles. Wnt activates Akt directly or through Wnt-1-induced secreted protein (WISP-1). The phosphorylation and inactivation of GSK-3β by Wnt may occur through protein kinase C (PKC) or through Akt activation.

Fig. 6

Signaling pathways that are involved in caspase activation during Alzheimer's disease. Caspase activation during Alzheimer's disease results in the cleavage of presenilin leading to an increase in the susceptibility of neurons to apoptosis with loss of β-catenin, poly(ADP-ribose)polymerase (PARP), and Bcl-2. Caspases can cleave amyloid precursor protein (APP) and the resulting C-terminal fragment C31 to produce hyperphosphorylation of tau protein (p-tau) as well as activation of glycogen synthase kinase-3β (GSK-3β). C31 and β-amyloid (Aβ) promotes the activation of caspases. Caspases also directly cleave tau protein to contribute to the formation of neurofibrillary tangles.