The neurotrophins and their role in Alzheimer's disease

Abstract

Besides being essential for correct development of the vertebrate nervous system the neurotrophins also play a vital role in adult neuron survival, maintenance and regeneration. In addition they are implicated in the pathogenesis of certain neurodegenerative diseases, and may even provide a therapeutic solution for some. In particular there have been a number of studies on the involvement of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in the development of Alzheimer's disease. This disease is of growing concern as longevity increases worldwide, with little treatment available at the moment to alleviate the condition. Memory loss is one of the earliest symptoms associated with Alzheimer's disease. The brain regions first affected by pathology include the hippocampus, and also the entorhinal cortex and basal cholinergic nuclei which project to the hippocampus; importantly, all these areas are required for memory formation. Both NGF and BDNF are affected early in the disease and this is thought to initiate a cascade of events which exacerbates pathology and leads to the symptoms of dementia. This review briefly describes the pathology, symptoms and molecular processes associated with Alzheimer's disease; it discusses the involvement of the neurotrophins, particularly NGF and BDNF, and their receptors, with changes in BDNF considered particularly in the light of its importance in synaptic plasticity. In addition, the possibilities of neurotrophin-based therapeutics are evaluated.

Keywords: Alzheimer's disease; BDNF; NGF; cholinergic basal forebrain.; synaptic plasticity.

Fig. (1)

Gross atrophy of the human brain in Alzheimer’s disease [b] compared with normal [a]. In moderate to severe Alzheimer’s disease, enlargement of the lateral ventricles is evident, due to cell loss, and thinning of the gyri, producing widened sulci. The hippocampus appears shrunken. Histochemical staining with certain dyes such as Thioflavin S make visible neurons containing neurofibrillary tangles [c] and extracellular amyloid plaques [d].

Fig. (2)

Production of Aβ by cleavage of APP (amyloid precursor protein). Beta-secretase and gamma secretase sequentially cleave APP to form Aβ, which then aggregates to form amyloid plaques.

Fig. (3)

ProNGF and NGF interactions with receptors. In normal brain (white arrows), proNGF is processed to NGF extracellularly by plasmin, and intracellularly by furins. NGF acts at TrkA, facilitated by p75NTR. This leads to acetylcholine release and activation of M1 muscarinic receptors which leads to increased alpha-secretase activity, which is counter to Aβ production. In Alzheimer brain (arrows in black) proNGF is not processed properly to NGF. The increased level of proNGF will lead to increased binding at p75NTR and probably sortilin, leading to a greater likelihood of cell death. Due to an increase in MMP9 activity NGF is degraded more quickly. Thus less acetylcholine will be released, less communication with other neurons, less activation of M1 receptors and an increase in beta-secretase activity. The latter will lead to an increase in Aβ formation. Length and thickness of arrows denotes strength of activity.

Fig. (4)

ProBDNF and BDNF interactions with receptors. In normal brain (white arrows), proBDNF is processed to BDNF extracellularly by plasmin, or intracellularly by furins or proconvertases. BDNF acts at TrkB facilitating LTP. This leads to synapse strengthening. In Alzheimer brain (arrows in black) proBDNF is downregulated (perhaps directly due to Aβ), thus BDNF levels are reduced. This will lead to a reduction in LTP and synapse formation. Length and thickness of arrows denotes strength of activity. Question marks denote unknowns.