5.3.1 Before reading the article:
Initially, Esteban puts the nature of Alzheimer's disease in perspective and highlights how much it affects the aged population. Within this brief introduction, he points us to the most characteristic pathophysiological hallmark of Alzheimer's disease: β-amyloid (Aβ) peptide accumulation. The Aβ peptide is a product of the proteolytic processing of the amyloid precursor protein (APP). Aβ formation is believed to lead to the production of β-amyloid plaques, which is a characteristic feature of Alzheimer's disease, and is independent of the presence of the Aβ peptide in plasma and cerebrospinal fluid. However, the paper by Kamenetz et al. (2003) states that Aβn could have a role in normal neuronal function. Evidence for this role comes from the fact that Aβn is normally synthesised by neurons and modulates excitatory transmission after N-methyl-D-aspartate (NMDA) (see Note A below) receptor activation. The investigators used organotypic (see Note B below) slice cultures to demonstrate that Aβ depresses fast synaptic transmission by NMDA and AMPA receptor activation. This result is consistent with the observed impairment of long-term potentiation (LTP) (see Note C below) after Aβ production. Finally, the author considers some important points, such as possible difficulties in interpreting the data obtained using some animal models, including gene knockouts.
A Glutamate is the most common excitatory neurotransmitter in the brain. Glutamate exerts its effect by binding to glutamate receptors (ionotropic and metabotropic). The ionotropic receptors are ligand-gated ion channels, and are subdivided into three groups (AMPA, NMDA and kainate receptors) based on their pharmacology and structural similarities. NMDA receptors are composed of assemblies of NR1 subunits and NR2 subunits. Both subunits are required to form functional channels. The glutamate binding domain is formed at the junction of NR1 and NR2 subunits (hence the need for both subunits). In addition to glutamate, the NMDA receptor requires the co-agonist glycine to bind, in order for the receptor to function. At resting membrane potentials, NMDA receptors are inactive. NMDA receptor activation leads to a calcium influx into the postsynaptic cells, a signal thought to be crucial for the induction of NMDA-receptor-dependent long-term potentiation (LTP) and long-term depression (LTD).
B The use of experimental models in the study of normal human biology and associated disease progression has led to the development of organotypic slices. A model system should reproduce both the 3-D organisation and the differentiated function of any given organ, but at the same time allow experimental intervention. Organotypic slices fulfil these requirements, in that they approximate organ structure and function in vitro and enable systematic analyses of the molecular contributions of the multiple cell types present.
C Long-term potentiation (LTP) is the enduring facilitation of synaptic transmission that occurs following the activation of a synapse by high-frequency stimulation of the presynaptic neuron. LTP has been suggested to be the functional basis of the neuronal changes that underlie learning and memory. It has been found to occur in several regions of the mammalian brain, including the hippocampus, one of the major brain regions responsible for processing memories. LTP is one of the first examples of a neural mechanism that may affect cognitive function. For further details and information about the relevance of LTP, the following paper is strongly recommended: Bliss, T. V. and Lomo, T. (1973) ‘Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path’, Journal of Physiology, 232(2), pp. 331–356.
Now read Neural Ageing Article 2: Esteban, J. A. (2004) ‘Living with the enemy: a physiological role for the β-amyloid peptide’, Trends in Neurosciences, 27, pp. 1–3.
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