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  Genes, Brain and Behavior (2008),  7   (Suppl. 1), 43–56   # 2007 The Authors Journal compilation # 2008 Blackwell Publishing Ltd  Review Neurotrophic factors in Alzheimer’s disease: role ofaxonal transport K. Schindowski* , † , ‡ , K. Belarbi † , ‡ and L. Bue´ e † , ‡ †  InstitutNationaldelaSante ´  etdelaResearchMe ´ dicale(INSERM) U837, and   ‡  Faculte ´  de Me ´ decine, Institut de Me ´ decine Pre ´ dictive etRecherche The ´ rapeutique, Universite ´  Lille 2,Lille Cedex, France *Corresponding author: K. Schindowski, INSERM, U837,Place de Verdun, Lille Cedex, Lille, France. E-mail:  Neurotrophic factors (NTF) are small, versatile proteinsthat maintain survival and function to specific neuronalpopulations. In general, the axonal transport of NTF isimportant as not all of them are synthesized at the site ofits action. Nerve growth factor (NGF), for instance, isproduced in the neocortex and the hippocampus andthen retrogradely transported to the cholinergic neuronsof the basal forebrain. Neurodegenerative dementias likeAlzheimer’s disease (AD) are linked to deficits in axonaltransport. Furthermore, they are also associated withimbalanced distribution and dysregulation of NTF. Inparticular, brain-derived neurotrophic factor (BDNF)plays a crucial role in cognition, learning and memoryformation by modulating synaptic plasticity and is,therefore, a critical molecule in dementia and neurode-generative diseases. Here, we review the changes of NTFexpression and distribution (NGF, BDNF, neurotrophin-3,neurotrophin-4/5 and fibroblast growth factor-2) andtheir receptors [tropomyosin-related kinase (Trk)A, TrkB,TrkC and p75 NTR ] in AD and AD models. In addition, wefocus on the interaction with neuropathological hall-marks Tau/neurofibrillary tangle and amyloid- b  (Abe-ta)/amyloid plaque pathology and their influence onaxonal transport processes in order to unify AD-specificcholinergic degeneration and Tau and Abeta misfoldingthrough NTF pathophysiology. Keywords: Abeta, APP, BDNF, cholinergic neurons, demen-tia, neurodegeneration, NGF, NT-3, NT-4/5, Tau Received13July2007,acceptedforpublication19October2007  From ‘healthy’ aging to Alzheimer’s disease Alzheimer’sdisease(AD)isaneurodegenerativedisorderthatis characterized by global cognitive decline including a pro-gressive loss of memory, orientation and reasoning. Theneurologist and psychiatrist Alois Alzheimer extensivelydescribed a dementia syndrome of his patient D. Auguste,whom he treated in Frankfurt am Main, Germany at thebeginning of the past century (Jarvik & Greenson 1987). Herecordedarapidlyprogressingmemorylossofthe52-year-oldwoman. After her death, he examined her brain and foundhistological changes that are specific for AD.Age-associated dementias like AD are becoming more andmore important in industrialized countries as life expectancyincreased by 2 years per decade during the recent 20 years(Klenk  et al.  2007). The incidence of age-associated demen-tias is about 1.3% of the total population of Western Europe;among them, AD is the most common, affecting 50% of alldementedpatients(Ferri etal. 2005;Hofman etal. 1991).Thisis likely to increase dramatically in the next 35 years. Accord-ing to recent estimations, the number of people with demen-tia over the age of 60 will be approximately doubled in 2040.An irreversible loss of cognitive and mental abilities is theprognosis of this disorder. In later stages, demented patientsare helpless and require full-time nursing care. Besides thepersonalandfamilialtragediesthatareanaspectofdementia,AD and other dementias are a financial problem for the healthservice and, thereby, a burden for the whole social commu-nity. And this cost will rise in future as more and morepersons are aging and becoming older. Neuropathological changes in the AD brain Histologically, the neurodegeneration is distinguished byneuropathological changes and deposits of misfolded pro-teins, mainly consisting of hyperphosphorylated Tau in neu-rofibrillary tangles and amyloid- b  (Abeta) in the form of senileplaques and deposits in cerebral blood vessels. Neurofibrillary tangles  Neurofibrillary tangles consist of hyperphosphorylated Tauproteins that aggregate inside neurons along neurites –observed as neuropil threads – and finally in the soma. Tauproteins belong to the microtubule-associated protein family.They are mainly found in neurons. Nonneuronal cells usuallydisplay trace amounts, but insome diseases, accumulation oftau in glial cells is detected (Bergeron  et al.  1997).Re-use of this article is permitted in accordance with theCreative Commons Deed, Attribution 2.5, which does notpermit commercial exploitation. doi: 10.1111/j.1601-183X.2007.00378.x  43  The human Tau gene is located on chromosome 17 andcontains 16 exons. Alternative splicing of three of theseexons (exons 2, 3 and 10) allows for six combinations(2  3  10  ; 2 þ 3  10  ; 2 þ 3 þ 10  ; 2  3  10 þ ; 2 þ 3  10 þ and 2 þ 3 þ 10 þ ) in the human brain. Tau proteins constitutea family of six isoforms, which range from 352 to 441 aminoacids and have a high number of phosphorylation sites. Tauproteins bind microtubules through repetitive regions in theirC-terminal part. These repetitive regions are the repeatdomains (R1–R4) encoded by exons 9–12. The three (3R) orfourcopies(4R)aremadeofahighlyconserved18-aminoacidrepeat separated from each other by less conserved 13- or14-amino acid interrepeat domains. Furthermore, the six Tauisoforms appear not to be equally expressed in neurons (fordetailed review, see Sergeant  et al.  2005). Tau proteins areknown to act as promoters of tubulin polymerization  in vitro  and are involved in axonal transport.A couple of evidences support a role for the microtubule-bindingdomaininthemodulationofthephosphorylationstateof Tau proteins. In a low phosphorylated state, Tau binds tomicrotubules through the microtubule-binding domains andstabilizes their polymerization and assembly. However,microtubule assembly depends partially upon the phosphor-ylationstateasphosphorylatedTauproteinsarelesseffectivethan nonphosphorylated Tau proteins on microtubule poly-merization.Phosphorylationinsideandoutsidethemicrotubule-binding domains can strongly influence tubulin assembly bymodifyingtheaffinitybetweenTauandmicrotubules.However,properly assembled microtubules are essential to maintainaxonal transport processes.MostofthekinasesinvolvedinTauphosphorylationincludemitogen-activated protein kinase (MAPK), Tau-tubulin kinaseandcyclin-dependent kinase.Stress-activatedproteinkinaseshave also been recently linked to Tau phosphorylation.Glycogen synthase kinase-3 b  (GSK-3 b ) is a Tau kinase thatis able to phosphorylate both non-Ser/Thr-Pro sites and Ser/ Thr-Pro sites.In numerous neurodegenerative disorders, Tau proteinsaggregate into intraneuronal filamentous inclusions. In AD,these filaments are named paired helical filaments (PHF).Fewphosphorylation-dependentantibodiessuchasAT100,AP422 or TG3/MC1 antibodies only detect PHF-tau, demon-strating the presence of abnormal phosphorylated sites. Withthe exception of Ser422, these phosphorylated sites found inPHF-tau are in addition conformation-dependent epitopes(Sergeant  et al.  2005). There is a direct relationship betweenhyperphosphorylation, abnormal phosphorylation and Tauaggregation, but it remains to be determined whether phos-phorylation is a cause or a consequence in the aggregationprocess.During normal aging, Tau hyperphosphorylation occurs in thetransentorhinal cortex and spreads from here through theentorhinal cortex to the hippocampus (Braak & Braak 1991;Delacourte  et al.  2002). Once the hippocampus is reached,amyloidplaquesmayoccur,andthentheTaupathologyspreadsovertothebasalforebrainandseveralcorticalareasinadistinctpatternalong neuronal projections. Onlythe coexistence of Tauand amyloid pathologies is determined as AD.To comprehend the role and mechanism of Tau pathologyin AD, it is important to understand the normal function andprocessing of the Tau protein and the abnormal posttransla-tional processing of Tau in tauopathies. Mutations in the Taugene have been found in several non-AD tauopathies andautosomal-dominant neurodegenerative disorders thatexhibit extensive neurofibrillary pathology. However, Taupathology observed in aging and AD is sporadic and notrelated to any mutation. Amyloid plaques  A major feature of both sporadic and familial forms of AD isthe accumulation and deposition of Abeta – a peptide of39–43 residues – within the brain tissue of AD sufferers. Theaccumulation of Abeta is thought to play a pivotal role inneuronal loss or dysfunction through a cascade of events thatinclude the generation of free radicals, mitochondrial oxida-tive damage and inflammatory processes. The primary eventthat results in the abnormal accumulation of Abeta is thoughtto be the dysregulated proteolytic processing of its parentmolecule, the amyloid precursor protein (APP) located onchromosome 21 (Selkoe 2001). The APP molecule is a trans-membrane glycoprotein that is proteolytically processed bytwo competing pathways, the nonamyloidogenic and theamyloidogenic (Abeta-forming) pathways. How these path-ways are regulated remain unclear. Three major secretasesare postulated to be involved in the proteolytic cleavage ofAPP. These include  a -secretase (of which the metallopro-teases a disintegrin and metalloprotease (ADAM)17/TNF-alpha converting enzyme (TACE) and ADAM10 are likelycandidates), beta APP cleaving enzyme (BACE, formallyknown as  b -secretase) and the  g -secretase. The  a -secretasecleaves within the Abeta domain of APP, thus precluding theformation of Abeta and generating nonamyloidogenic frag-ments and a secreted form of APP ( a -APPs). In the amyloido-genic pathway, BACE cleaves near the N-terminus of theAbetadomainontheAPPmolecule,liberatinganothersolubleform of APP,  b -APP, and a C-terminal fragment (C99) con-taining the whole Abeta domain. The last step in the amyloi-dogenicpathwayistheintramembranouscleavageoftheC99fragment by  g -secretase, to liberate a number of Abetaisoforms of 39- to 43-amino acid residues in length (Verdile et al  . 2004). The same  g -secretase complex that generatesAbeta may also generate the APP intracellular domain. Themost common isoforms are Abeta 40  and Abeta 42 ; the shorterform is typically produced by cleavage that occurs in theendoplasmic reticulum, while the longer form is produced bycleavage in the trans-Golgi network. The Abeta 40  form is themore common of the two, but Abeta 42  is the more fibrillo-genic because of its more hydrophobic nature and is, thus,associated with disease states. The  g -secretase enzyme isthought to be an aspartyl protease that has the unusual abilityto regulate intramembrane proteolysis (for review, see Wolfe& Kopan 2004). The mechanism of  g -secretase activity is notyet known. Four components of the  g -secretase complex,presenilins, nicastrin, anterior pharynx defective (aph-1) andpresenilin enhancer 2 (pen-2), have been identified.Recently, it was shown that Abeta 42  aggregates intooligomers within endosomal vesicles and along microtubulesof neuronal processes, in cultured neurons, inAPP transgenicmice and in human AD brain (Takahashi  et al.  2004). The 44  Genes, Brain and Behavior   (2008),  7  (Suppl. 1), 43–56 Schindowski et al.  oligomers that form on the amyloid pathway may be thecytotoxic species rather than the mature fibrils (Kayed  et al. 2003). Subsequently, anterograde axonal transport deliversAbeta to plaques (Lazarov  et al.  2002; Stokin  et al.  2005).The sites of APP processing and Abeta release have yetremained unclear. Some studies speculate that the axon isthe site of Abeta production (Muresan and Muresan, 2006).According to this, amyloid deposition would increase if pooraxonal transport delays the progress of APP and its process-ing enzymes through the axon (Stokin  et al.  2005) butdecreases when overexpression of BACE shifts Abeta gen-eration away from the axon and synapse into the cell soma(Lee etal. 2005a).Butnotallreportscanreproducepartofthismodel, in which APP is cotransported with its processingenzymes (Goldsbury  et al.  2006; Lazarov  et al.  2005). SomeAbeta release occurs at synapses (Lazarov  et al.  2005; Sheng et al.  2002) and appears to be dependent on synaptic activity(Cirrito  et al.  2005). However, the occurrence of plaques inwhite matter tracts that lack synaptic input and the release ofAbetainprimaryneuronalculturesthatlacksynapsessuggestthat Abeta might be released from more proximal sites too(Qiu  et al.  2001; Wirths  et al.  2007). Indeed, if all Abeta re-lease were at presynaptic endings, impairing axonal transportshould decrease amyloid deposition instead of increasing it.Autosomal-dominant mutations in APP cause hereditaryearly-onset AD, likely as a result of altered proteolyticprocessing. Increase in either the total Abeta levels or therelative concentrations of both Abeta 40  and Abeta 42  has beenimplicated in the pathogenesis of both familial and sporadicAD (Lue  et al.  1999). Three hypotheses for the pathogenesis of AD  The underlying molecular mechanisms of AD pathogenesishave not yet been identified; therefore, three major hypoth-eses have been advanced regarding the primary cause. Theearliest hypothesis suggests that deficiency in cholinergicsignaling initiates the progression of the disease. Two alter-native misfolding hypotheses instead propose that either Tauprotein or Abeta initiates the cascade.The oldest hypothesis is the ‘cholinergic hypothesis’. Aparticular hallmark of AD is the specific neurodegeneration ofcholinergic neurons leading to a loss of the neurotransmitteracetylcholine (ACh). Loss of cholinergic neurons seems to bespecifically associated with typical clinical symptoms, likememory deficits, impaired attention, cognitive decline andreduced learning abilities (Hasselmo & Stern 2006; Kar  et al. 2004). All the first-generation therapeutics against AD werebased on this hypothesis and work to preserve ACh byinhibiting its degrading enzyme acetylcholine esterase(AChE). These medications have not led to a cure. In allcases, they have served to only treat symptoms of thedisease and can delay the progression of AD by 1–2 yearsbut failed to reverse it. Therefore, it was concluded that AChdeficiencies may not be directly causal. More recently,cholinergic effects have been proposed as a potential caus-ative agent for the formation of plaques and tangles (Shen2004).Later theories center on the effects of the misfolded andaggregated proteins Tau and Abeta. The hypothesis that Tauis the primary causative factor has been grounded on the factthat AD neuropathology starts in most individuals with hyper-phosphorylatedTauandneurofibrillarytangleslongbeforethefirst signs of Abeta occur (Braak & Braak 1991; Delacourte et al.  2002). Nevertheless, accumulations of amyloid arefrequently found in the cortex of nondemented individualsin the absence of neurofibrillary changes. A mechanism forneurotoxicity could be that hyperphosphorylated and aggre-gated Tau impairs axonal transport in murine Tau transgenicmodels (Ishihara  et al.  1999; Lewis  et al.  2000; Probst  et al. 2000), invertebrate models (Chee  et al.  2005; Kraemer  et al. 2003; Mudher  et al.  2004) and cellular models (Mandelkow et al.  2004; Seitz  et al.  2002; Stamer  et al.  2002). Problemswith axonal transport are believed to be a major cause leadingto the symptoms and pathology observed in AD and otherneurodegenerative dementias (Adalbert  et al.  2007). How-ever,uptonow,thepreexistenceofTaupathologybeforetheoccurrence of Abeta pathology has not been shown in anyexperimental Tau model.Abeta protein is a key molecule in the pathogenesis of AD.The tendency of Abeta to aggregate, its reported neurotox-icity and genetic linkage studies has led to the amyloidcascade hypothesis (Hardy & Allsop 1991). Inthis hypothesis,an increased production of Abeta results in neurodegenera-tion and ultimately dementia through a cascade of events(Verdile  et al.  2004). Amyloidogenic mouse models haveestablished that overproduction of Abeta leads to dystrophicaxons and dendrites around amyloid plaques (Brendza  et al. 2003; Tsai  et al.  2004a). Treatment of cultured neurons withfibrillar Abeta results in an increase of Tau phosphorylation,leading to a loss of microtubule-binding capacity and accumu-lation of Tau in the somatodendritic compartment (Busciglio et al.  1995). Moreover, apolipoprotein E4 (ApoE4), the majorgenetic risk factor for AD, leads to excess amyloid build up inthe brain before AD symptoms arise. Thus, Abeta depositionprecedes clinical AD (Polvikoski  et al.  1995).Advances intheunderstanding ofAD pathogenesisprovidestrong support for a modified version of the amyloid hypoth-esis, which is now often referred to as the Abeta cascadehypothesis. The basic tenant of this modified hypothesis isthat an intermediate misfolded form of Abeta, neither a solu-ble monomer nor a mature aggregated polymer but anoligomeric species, triggers a complex pathological cascadeleading to neurodegeneration (Barghorn  et al.  2005; Kokubo et al.  2005).The relationship between APP, axonal transport and aber-rant Abeta processing is not as easy as for Tau. Axonopathyand transport deficit can be detected long before extracellularAbeta deposition in AD patients and in a mutant APP mousemodel (Stokin  et al.  2005). Overexpression of human APP695also impairs specific components of axonal transport inDrosophila and mice (Gunawardena & Goldstein 2001; Salehi et al.  2006). In mice, this leads to degeneration of basalforebrain cholinergic neurons (BFCN). Conversely, Abetaitself might impair axonal transport, possibly as oligomericAbeta 42  in microtubule-associated endosomal vesicles(Hiruma  et al.  2003; Maloney  et al.  2005; Takahashi  et al. 2004). In conclusion, impairment of axonal transport might bea cause or an effect of aberrant Abeta production or, in somecases, result from APP overexpression (Adalbert  et al.  2007). Genes, Brain and Behavior   (2008),  7  (Suppl. 1), 43–56  45 Neurotrophins in AD  The latter two theories point out the relevance of axonaltransport for proper neuronal function. Finally, ApoE4, themajor risk factor for sporadic AD, may directly disrupt thecytoskeleton and hence impair axonal transport also (Mahley et al.  2006). Here, we give some insights into how neuro-trophins may be the actors allowing to link between cholin-ergic degeneration, amyloid and Tau pathologies and axonaltransport. Neurotrophins: the NGF family The most prominent members of the mammalian neuro-trophin family are nerve growth factor (NGF), brain-derivedneurotrophic factor (BDNF), neurotrophin-3 (NT-3) andneurotrophin-4/5 (NT-4/5). They activate various cell signal-ing pathways by activating two types of membrane-boundreceptors, Trk (actually ‘tropomyosin-related kinase’ butrecently ‘tyrosine receptor kinase’ is also used: TrkA, TrkBand TrkC) and p75 NTR . These neurotrophins are synthesizedasproneurotrophinsthatallbindtothep75 NTR .In theiractivecleaved form, each neurotrophin selectively activates one ofthree types of Trk receptors (Fig. 1), NGF activates TrkA, NT-3 activates TrkC, while both BDNF and NT-4 activate TrkBreceptors (Patapoutian & Reichardt 2001). The role ofproneurotrophins and neurotrophins appears to be contra-dictory: while neurotrophins maintain survival and function,to certain neuronal populations, proneurotrophins trigger celldeath through p75 NTR (Friedman 2000).These neurotrophic factors (NTF) are small, versatile pro-teins that maintain neuronal survival, axonal guidance, cellmorphology and play key roles in cognition and memoryformation. During embryonic development, NTF are essentialfortheproperarchitectureandfunctionofthebrain.Knockoutmice for NGF, BDNF and NT-3 are all fatal and exhibit severeneuraldefects.Subsequenttoneuronalinjuryandlesions(likecerebral ischemia), NTFs are upregulated and are involved inhealing and neurogenesis.Axonal transport processes are essential for proper NTFsignaling. Nerve growth factor, for example, is synthesizedfar away from its site of action. Vesicles containing NTF andtheir relevant receptors are shipped along neuronal projec-tions throughout the brain as summarized in Table 1. How-ever, most neurodegenerative dementias are linked tofailures in axonal transport and – not surprisingly – themajority of them are associated with impaired regulationand imbalance of NTF. Neurotrophins and their receptors in AD Nerve growth factor  Pro-NGF is the predominant form of NGF in the human androdent brain, whereas mature NGF can be hardly detected.In AD, pro-NGF is increased in frontal and occipital cortex(Crutcher  et al.  1993; Fahnestock  et al.  2001; Hellweg  et al. 1998; Peng  et al.  2004) and in hippocampus (Hock  et al. 2000a; Narisawa-Saito  et al.  1996; Scott  et al.  1995), whilea loss is observed in the basal forebrain (Mufson  et al.  1995;Scott  et al.  1995). The amount of NGF messenger RNA(mRNA) is not altered in AD (Fahnestock  et al.  1996; Goedert et al.  1986, 1989; Jette  et al.  1994). A decrease of retrogradetransport could explain this observation, leading to an accu-mulation of NGF at the sites of its production (hippocampusand neocortical areas) and a deficiency at the NGF transportterminus, the BFCN.In the absence of NGF, cholinergic neurons show cellshrinkage, reduction in fiber density and downregulation oftransmitter-associated enzymes [e.g. choline-acetyl transfer-ase (ChAT) and AChE], resulting in a decrease of cholinergictransmission (Svendsen  et al.  1991). In parallel, rats showa decrease in ChAT and TrkA mRNA after fimbria transectionthat can be restored by NGF treatment (Venero  et al.  1994).InAD,areductionofChATandAChEactivityandBFCNsizeand number was observed (Arendt  et al.  1983; Kasa  et al. 1997; Loy  et al.  1990; Perry  et al.  1992; Treanor  et al.  1991),implicating a severe cholinergic degeneration. Therefore, theclassical AD therapy was treatment with AChE inhibitors thatenhance neuronal transmission by increasing the availabilityof ACh at the receptors. This effect is beneficial to stabilizecognitive function and to improve or stabilize many behavioralsymptoms of AD at a steady level during a 1-year period oftreatment (Giacobini 2003; Wynn & Cummings 2004). Cur-rently, there is an ongoing gene therapy trial using NGF-grafted autologous fibroblasts that were injected into thebasal nucleus of Meynert (nbM) (Tuszynski  et al.  2005) withthe aim to rescue the BFCN of AD patients.Moreover,alossoftheNGFreceptorTrkAwasfoundinthebasal forebrain (Boissiere  et al.  1997; Chu  et al.  2001;Ginsberg  et al.  2006a; Mufson  et al.  1997, 2000; Salehi et al.  1996) and in the cortex (Counts  et al.  2004; Hock et al.  1998; Savaskan  et al.  2000) of AD brains. Figure 1: The neurotrophins and their receptors. 46  Genes, Brain and Behavior   (2008),  7  (Suppl. 1), 43–56 Schindowski et al.
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