Neurotrophic factors in Alzheimer’s disease: role of axonal transport

Abstract

Neurotrophic factors (NTF) are small, versatile proteins that maintain survival and function to specific neuronal populations. In general, the axonal transport of NTF is important as not all of them are synthesized at the site of its action. Nerve growth factor (NGF), for instance, is produced in the neocortex and the hippocampus and then retrogradely transported to the cholinergic neurons of the basal forebrain. Neurodegenerative dementias like Alzheimer's disease (AD) are linked to deficits in axonal transport. Furthermore, they are also associated with imbalanced distribution and dysregulation of NTF. In particular, brain-derived neurotrophic factor (BDNF) plays a crucial role in cognition, learning and memory formation by modulating synaptic plasticity and is, therefore, a critical molecule in dementia and neurodegenerative diseases. Here, we review the changes of NTF expression and distribution (NGF, BDNF, neurotrophin-3, neurotrophin-4/5 and fibroblast growth factor-2) and their receptors [tropomyosin-related kinase (Trk)A, TrkB, TrkC and p75 NTR ] in AD and AD models. In addition, we focus on the interaction with neuropathological hallmarks Tau/neurofibrillary tangle and amyloid-b (Abeta)/amyloid plaque pathology and their influence on axonal transport processes in order to unify AD-specific cholinergic degeneration and Tau and Abeta misfolding through NTF pathophysiology.

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

“…To this regard, the finding that the retrograde transport of I-125-NGF and activated Trk receptors is inhibited by colchicine-a drug that interferes with the polymerization of microtubules (Watson et al, 1999;Sandow et al, 2000)-suggests that an altered function of tau protein may account for age-related deficiency of long-range NTF signaling in cholinergic neurons. Actually, the hypothesis that the failure of tau-mediated axonal transport might be responsible for the lack of trophic support in aged or AD brains (Salehi et al, 2004;Niewiadomska et al, 2006a;Schindowski et al, 2008) is supported by several evidences. An endosome-containing activated TrkA following NGF binding is transported from the presynaptic terminals axons of the BFCNs to the cell body via a microtubule-dependent mechanisms (Watson et al, 1999;Delcroix et al, 2004; Figure 1 Scheme representing the NGF-dependent hippocampal neuronal model.…”

Alzheimer disease and neuroplasticity: New approaches and new targets in pharmacotherapy

“…In AD, reduction of ChAT and AchE activity was observed. Thus, classical AD treatment with AchE inhibitors enhances neuronal transmission by increasing the availability of acetylcholine at the receptors (91). The role of p75 NTR is not clear.…”

“…Results from a number of studies indicate that neurotrophins and their receptors have a key function in protection of synaptic formation and reliable neurotransmission in CNS. Indeed, neurotrophic factors are key regulators not only for development, maintanence and survival, but also for cognition, formation and storage of normal memory (91). The most prominent members of the mammalian neurotrophin family are nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) (please see, Table 2).…”

“…In their active cleaved form, each neurotrophin selectively activates one of three types of Trk receptors. NGF activates TrkA, NT-3 activates TrkC, while BDNF and NT-4 activate Trk B receptors (91,92).…”

Different effects of soluble and aggregated amyloid β42 on gene/protein expression and enzyme activity involved in insulin and APP pathways

“…Alzheimer´s dementia (AD) is not anymore characterised just by the accumulation and deposition of amyloid beta (Aβ) peptides and hyperphosphorylated tau proteins within the brain; in the mean time, it is also characterised by synaptic loss (Small, 2004), imbalanced metabolism (Schindowski et al, 2008;Grünblatt et al, 2010), abnormal protein cross-linking (Munch et al, 1998;Wang et al, 2008), and disturbance of the insulin signalling pathway (Hoyer et al, 1994;de la Monte et al, 2009;. Although more and more factors are found to be involved in AD, excessive Aβ 42 deposition is still considered to play a major role in AD.…”