O assunto é Alzheimer no "The New England Journal of Medicine"

Este tópico foi retirado do "E-resident Bulletin" do The New England Journal of Medicine Vol. 362, No. 4, January 28, 2010! Aproveite e cadastre-se! É grátis!


“Many molecular lesions have been detected in Alzheimer's disease, but the overarching theme to emerge from the data is that an accumulation of misfolded proteins in the aging brain results in oxidative and inflammatory damage, which in turn leads to energy failure and synaptic dysfunction.”
H.W. Querfurth and F.M. LaFerla, “Mechanisms of Disease: Alzheimer's Disease”


1. Mechanisms of Alzheimer's Disease
REVIEW ARTICLE, Mechanisms of Disease: Alzheimer's Disease, H.W. Querfurth and F.M.



ABSTRACT: More than 35 million people worldwide — 5.5 million in the United States — have Alzheimer's disease, a deterioration of memory and other cognitive domains that leads to death within 3 to 9 years after diagnosis. Alzheimer's disease is the most common form of dementia, accounting for 50 to 56% of cases at autopsy and in clinical series. Alzheimer's disease combined with intracerebral vascular disease accounts for another 13 to 17% of cases. (FULL TEXT AVAILABLE ON THE WEBSITE)


Clinical Pearl
What is the mechanism through which cholinesterase inhibitors treat Alzheimer's disease?

Pharmacologic stimulation of the postsynaptic primary motor cortex (M1) subtype of muscarinic acetylcholine receptors activates protein kinase C, favoring processing of amyloid precursor protein without producing amyloid. Furthermore, activation of nicotinic acetylcholine receptors or M1 receptors limits tau phosphorylation. Although cholinesterase inhibitors improve neurotransmission and provide mild palliative relief in Alzheimer's disease, they lose efficacy over time.



What are the primary pathological features of Alzheimer's disease?
Cerebral plaques laden with β-amyloid (Aβ) peptide, dystrophic neuritis in neocortical terminal fields, and neurofibrillary tangles in medial temporal-lobe structures are important pathological features of Alzheimer's disease. Loss of neurons and white matter, congophilic (amyloid) angiopathy, inflammation, and oxidative damage are also present. An imbalance between production and clearance, and aggregation of peptides, causes Aβ to accumulate, and this excess may be the initiating factor in Alzheimer's disease.



What are neurofibrillary tangles?
Neurofibrillary tangles, which are filamentous inclusions in pyramidal neurons, develop in Alzheimer's disease. The number of neurofibrillary tangles is a marker of the severity of Alzheimer's disease. The major component of the tangles is an abnormally hyperphosphorylated and aggregated form of tau. Normally an abundant soluble protein in axons, tau promotes assembly and stability of microtubules and vesicle transport. Hyperphosphorylated tau is insoluble, lacks affinity for microtubules, and self-associates into paired helical filament structures. Like Aβ oligomers, intermediate aggregates of abnormal tau molecules are cytotoxic and impair cognition.