Pathways towards and away from Alzheimer's disease

Abstract

Slowly, but surely, Alzheimer's disease (AD) patients lose their memory, their cognitive abilities and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. While drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise is increasing optimism that effective preventative and therapeutic strategies are in the offing.Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries; the risk of AD dramatically increases in individuals beyond the age of 70 and it is predicted that the incidence of AD will triple within the next 50 years (www.alz.org). There can be other causes of memory loss and definitive diagnosis of AD therefore requires postmortem examination of the brain, which must contain sufficient numbers of "plaques" and "tangles" to qualify as AD 1, 2 . Plaques are extracellular deposits of fibrils and amorphous aggregates of amyloid β-peptide (Aβ); diffuse deposits of Aβ are also present in high amounts. Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibit hyperphosphorylation and oxidative modifications. Plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behaviors such as the entorhinal cortex, hippocampus, basal forebrain and amygdala. Brain regions with plaques typically exhibit reduced numbers of synapses, and neurites associated with the plaques are often damaged, suggesting that Aβ damages synapses and neurites. Neurons that employ glutamate or acetylcholine as neurotransmitters appear to be particularly affected, but neurons that produce serotonin and norepinephrine are also damaged. This review focuses on the molecular and cellular abnormalities that occur in the brain in AD, how they result in synaptic dysfunction and cell death, and how they can be counteracted. Central to the disease is altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Neurons that degenerate in AD exhibit increased oxidative damage, impaired energy metabolism and perturbed cellular calcium homeostasis; Aβ appears to be an important instigator of these abnormalities. Genetic and environmental factors can determine one's risk for and an understanding of these risk factors and how they modify the amyloid cascade is leading to the development of interventions for the prevention and treatment of AD that range from changes in diet and lifestyle, to vaccines and drugs.

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…The presenilins are essential for cleavage of APP at the C-terminus of amyloid b-peptide, the final step in amyloid b-peptide production. 81 Studies of neurons expressing normal or mutant forms of presenilin-1 suggest a role for impaired ability of neurons to induce NF-kB activation under conditions of oxidative stress in the pathogenesis of Alzheimer's disease. 75 An abnormal NF-kB response occurs in neurons expressing mutant presenilin-1 such that it is activated rapidly, but then drops to very low levels for a prolonged time period.…”

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

“…Behavioral abnormalities in AD result from dysfunction and death of neurons in brain regions involved in cognition and mood such as the hippocampus, amygdala and associated cortical regions. These brain regions suffer from degeneration of synapses and neurons, which are associated with extracellular accumulations of amyloid β-peptide (Aβ) (plaques) and intraneuronal filamentous aggregates of the microtubule-associated protein tau (neurofibrillary tangles) (Selkoe and Schenk, 2003;Mattson, 2004). Aβ is a 40−42 amino acid proteolytic cleavage product of an integral membrane protein, the amyloid precursor protein (APP).…”

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

“…Development of effective Alzheimer's disease (AD) therapy is urgently required because AD currently affects nearly 2% of the population in industrialized countries (Mattson, 2004). AD is characterized clinically by progressive memory impairment and pathologically by senile plaques, neurofibrillary tangles, and neuronal death.…”