Tau phosphorylation in Alzheimer's disease: potential involvement of an APP-MAP kinase complex.

The two predominant pathological concomitants of Alzheimer's disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (beta-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1.

PKR activation in neurodegenerative disease.

Interferon-inducible, double-stranded RNA-dependent protein kinase PKR is well known as an early cellular responder to viral infection. Activation of PKR has been associated with a number of downstream cell stress and cell death events, including a generalized shutdown of protein translation, activation of caspase-8, participation in JNK and p38 MAPK pathways, activation of NF-kappaB, etc. Recently, the activation of PKR has also been described in several neurodegenerative diseases, including Huntington disease, Alzheimer disease, and amyotrophic lateral sclerosis.

Increased hippocampal neurogenesis in Alzheimer's disease.

Neurogenesis, which persists in the adult mammalian brain, may provide a basis for neuronal replacement therapy in neurodegenerative diseases like Alzheimer's disease (AD). Neurogenesis is increased in certain acute neurological disorders, such as ischemia and epilepsy, but the effect of more chronic neurodegenerations is uncertain, and some animal models of AD show impaired neurogenesis. To determine how neurogenesis is affected in the brains of patients with AD, we investigated the expression of immature neuronal marker proteins that signal the birth of new neurons in the hippocampus of AD patients.

Activation of the cell stress kinase PKR in Alzheimer's disease and human amyloid precursor protein transgenic mice.

Accumulation of amyloid beta peptides (Abeta) in the brain, which is a hallmark of Alzheimer's disease (AD), is associated with progressive damage to neuronal processes resulting in extensive neuritic dystrophy. This process may contribute to cognitive decline, but it is not known how Abeta elicits neuritic injury. Our analysis of AD brains and related transgenic mouse models suggests an involvement of the interferon-induced serine-threonine protein kinase, PKR, which is best known for its activation upon binding to double-stranded RNA.