The mammalian brain is extremely sensitive to alterations in cellular homeostasis as a result of environmental or physiological insults. In particular, hypoxic/ischemic challenges (i.e. reduced oxygen and/or glucose delivery) cause severe and detrimental alterations in brain function and can trigger neuronal cell death within minutes. Unfortunately, as we age, oxygen delivery to cells and tissues is impaired, thereby increasing the susceptibility of neurons to damage. Thus, hypoxic (neuronal) adaptation is significantly compromised during aging. Many neurological diseases, such as stroke, Alzheimer's disease (AD), Parkinson's disease and diabetes, are characterized by hypoxia, a state that is believed to only exacerbate disease progression. However, the contribution of hypoxia and hypoxia-mediated pathways to neurodegeneration remains unclear. This review discusses current evidence on the contribution of oxygen deprivation to AD, with an emphasis on hypoxia inducible transcription factor-1 (HIF-1)-mediated pathways and the association of AD with the cytoskeleton regulator cyclin-dependent kinase 5.

Background: Neuropathological mechanisms in Alzheimer disease (AD) are partially unknown. Results: Chronic JNK inhibition with a cell-permeable peptide (CPP) rescues memory deficits, LTP impairment, and reduces A␤ oligomers in a mouse model that mimics AD. Conclusion: JNK is crucial in AD neurodegenerative mechanisms. Significance: CPPs offer an important tool to interfere with neurodegeneration. JNK is a promising target against AD.

Alzheimer's disease (AD) is a major clinical concern, and the search for new molecules to combat disease progression remains important. One of the major hallmarks in AD pathogenesis is the hyperphosphorylation of tau and subsequent formation of neurofibrillary tangles. Several kinases are involved in this process. Amongst them, c-Jun N-terminal kinases (JNKs) are activated in AD brains and are also associated with the development of amyloid plaques. This study was designed to investigate the contribution of JNK in tau hyperphosphorylation and whether it may represent a potential therapeutic target for the fight against AD. The specific inhibition of JNK by the cell permeable peptide D-JNKI-1 led to a reduction of p-tau at S202/T205 and S422, two established target sites of JNK, in rat neuronal cultures and in human fibroblasts cultures. Similarly, D-JNKI-1 reduced p-tau at S202/T205 in an in vivo model of AD (TgCRND8 mice). Our findings support the fundamental role of JNK in the regulation of tau hyperphosphorylation and subsequently in AD pathogenesis.

Hypoxia is linked to changes in blood-brain barrier (BBB) permeability, and loss of BBB integrity is characteristic of many pathological brain diseases including stroke. In particular, astrocytes play a central role in brain homeostasis and BBB function. We investigated how hypoxia affects astrocyte survival and assessed whether VEGF release through hypoxia-inducible factor-1alpha (HIF-1alpha) induction plays a role in tolerance of these cells to insult. Thus primary astrocytes were subjected to normoxic (21% O(2)), hypoxic (1% O(2)), or near-anoxic (<0.1% O(2)) conditions in the presence or absence of glucose. Cell death was significantly initiated after combined oxygen glucose deprivation, and, surprisingly, astrocyte proliferation increased concomitantly. Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity, whereas oxygen and glucose deprivation accelerated HIF-1alpha accumulation. Unexpectedly, Hif-1alpha knockdown studies showed that elevated VEGF levels following increased insult was only partially due to HIF-1alpha induction, suggesting alternative mechanisms of VEGF regulation. Notably, endogenous VEGF signaling during insult was essential for cell fate since VEGF inhibition appreciably augmented cell death and reduced proliferation. These data suggest Hif-1 only partially contributes to VEGF-mediated astrocyte responses during chronic injury (as occurs in clinical hypoxic/ischemic insults) that may ultimately be responsible for disrupting BBB integrity.