Neurotrophic factors are key regulators not only for development, maintenance and survival but also for cognition, formation and storage of memory. In AD, NTF are dysregulated and because of impaired axonal transport, unevenly distributed.
In aging, Tau proteins are becoming increasingly hyperphosphorylated, leading to the formation of neurofibrillary tangles in the transentorhinal and entorhinal cortex. As not only Tau but also APP and ApoE4 play a key role in axonal transport (Adalbert et al.2007
), it would not be surprising that even at this early stage, deficits in transport processes can occur. Fascinatingly, the progression of neurofibrillary pathology in aging and in AD is identical to the retrograde transport pathways of BDNF in this neuroanatomical region. Under physiological conditions, BDNF is produced in the entorhinal cortex and shipped from here through the CA3 to the CA1–subiculum area, basal forebrain and amygdala, the next stations of neurofibrillary degeneration through the AD brain. One cannot exclude impaired transport of BDNF or downregulation of BDNF in tangle-bearing neurons in the aged brain, both leading to deficits in BDNF levels associated with possibly subclinical insufficiency in cognition and memory. Moreover, Tau pathology is the first visible occurrence of brain aging, but APP or low doses of Abeta or ApoE4 pathology may also influence the axonal transport of NTF at this stage. Furthermore, once the neurofibrillary pathology reaches the basal forebrain (occasionally already in Braak stage I), impaired retrograde transport of NGF could be the consequence, leading to an accumulation of NGF where it is synthesized (hippocampus and neocortex) and to a loss of NGF in the basal forebrain (). The well-known degeneration of BFCN in AD could be the outcome of this scenario. Additionally, cholinergic degeneration leads to a decrease in cholinergic innervation from fibers projecting from the basal forebrain to hippocampus and neocortex and thereby, to a decline of basal levels of BDNF expression with all its possible consequence on Tau phosphorylation. But what is more, NGF accumulation in the target regions may upregulate APP, but also may lead to increased signaling of pro-NGF through p75NTR
, which is increasingly expressed in the aged brain, and thus mediates cell death. Tau could function upstream to Abeta to modify APP transport. Blocking APP transport in vivo
increases Abeta generation and deposition. Some studies implicate that tau is required for Abeta toxicity, suggesting that tau lies downstream of Abeta.
Retrograde transport of NGF from the hippocampus to the basal forebrain
Not surprisingly, all major proteins involved with AD pathology (APP and Tau) or risk for sporadic AD (ApoE4) are associated somehow with axonal transport. However, using this knowledge for the development of therapy is not as simple.
The most important concern regarding a future therapy with NTF is the mode of delivery. Being small proteins with roughly no penetration of the blood–brain barrier, new avenues for therapy need to be found. An ongoing gene therapy focusing on NGF-grafted autologous fibroblasts that are implanted into the basal forebrain of AD patients predicts a slower progression of the dementia, some cognitive improvement and sprouting of axons on the site of injection (Tuszynski et al.2005
). Nevertheless, this therapy includes brain surgery and gene therapy and does not appear to be suitable as prophylactic cheap treatment for millions of aging people worldwide. Probably, NTF signaling is more likely a target for AD therapy than the NTFs themselves.
More data and support are needed to elucidate the mechanisms of NTF imbalance and dysregulation in AD. With this knowledge, we will be able to target pathways upstream NTF deregulation or deficits in axonal transport, thus starting the therapy before pathological imbalance of NTF occurs. This could include inhibitors of Tau kinases to avoid pathological Tau hyperphosphorylation that interferes with axonal transport processes and BDNF regulation. Unfortunately, chronic GSK-3β inhibition with lithium ions, which are used in therapy against bipolar disorder, appears not to have the predicted protective effect against AD (Bauer et al.2003
; Chuang 2004
; Manji et al.1999
), although it had been shown to regulate endogenous BDNF and NGF levels (Frey et al.2006a
Nevertheless, the potentials of neurofibrillary tangles (NFT) or drugs that act on their distribution or signaling should be considered carefully as future AD therapy.