Recent Understanding of the Molecular Mechanisms of Alzheimer's Disease

¹Experimental Neurology, Saarland University, Kirrbergerstrasse, 66421 Homburg/Saar, Germany

²Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrbergerstrasse, 66421 Homburg/Saar, Germany

³Neurodegeneration and Neurobiology, University, Kirrbergerstrasse, 66421 Homburg/Saar, Germany

*Corresponding Author:

Marcus OW Grimm
Saarland University, Kirrbergerstrasse
66421 Homburg/Saar, Germany
Tel: +49-6841-1647919
Fax: +49-6841-1647801
E-mail: marcus.grimm@uks.eu

Received December 08, 2011; Accepted January 18, 2012; Published January 22, 2012

Citation: OW Grimm M, Hartmann T (2012) Recent Understanding of the Molecular Mechanisms of Alzheimer’s Disease. J Addict Res Ther S5:004. doi:10.4172/2155-6105.S5-004

Copyright: © 2012 OW Grimm M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the aged population. Pathological hallmarks of AD are the presence of extracellular senile plaques and intracellular neurofibrillary tangles. Extracellular plaques consist of aggregated amyloid-β (Aβ) peptides derived from sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretase. Neurofibrillary tangles are composed of a hyperphosphorylated form of the microtubule-associated protein tau. This review summarizes the current understanding in the molecular mechanisms leading to Aβ generation as well as hyperphosphorylation of tau and the mechanisms of Aβ-induced neurotoxicity including Ca2+ dyshomeostasis, mitochondrial dysfunction, increased oxidative stress, cholinergic dysfunction and neuroinflammation finally resulting in neuronal/synaptic dysfunction and neuronal loss.

Alzheimer’s Disease – Epidemiology and Pathological Hallmarks

Alzheimer’s disease (AD) is the most common form of dementia in the elderly and is characterized in patients by an inexorably progression, causing problems with memory, thinking and behaviour. Currently 25 million people worldwide are estimated to be affected by AD with the highest number in North America, Latin America, Western Europe, China and the western pacific [1]. Epidemiological studies predict that the incidence of AD will increase due to increasing life expectancy to 42.3 million in 2020 and 81.1 million in 2040 [1,2], emphasizing AD as a major public health concern.

The two main histopathological hallmarks of AD are extracellular amyloid plaques and intracellular neurofibrillary tangles in vulnerable brain regions like hippocampus and cortex [3]. The amyloid plaques, also called senile plaques, are mainly composed of amyloid-beta peptides (Aβ), most of which are 38 to 43 amino acids long [4]. Aβ peptides are generated by sequential processing of the amyloid precursor protein (APP), a large type-I transmembrane protein [5] that belongs to an evolutionary conserved protein family including beside APP, the APP-like protein 1 (APLP1) and 2 (APLP2) in mammals [6,7] with the Aβ domain to be unique to APP [8]. The second characteristic pathological hallmark of AD, the intracellular neurofibrillary tangles, consist of an abnormally phosphorylated form of the microtubule-associated protein tau [9]. In contrast to amyloid plaques, which accumulate extracellularly in the brains of AD affected individuals and have been long believed to cause neuronal damage and cell death, neurofibrillary tangles are found inside neurons and their branching points like axons and dendrites [10,11].

Proteolytic Processing of APP

Amyloidogenic APP processing

Proteolytic processing of APP leading to Aβ peptides is a ubiquitous cellular process involving β- and γ-secretase activity (Figure 1). The first step in Aβ production is APP cleavage by β-secretase, generating the N-terminus of Aβ. BACE 1 (β-site APP cleaving enzyme, also called Asp2 or memapsin2) was identified as the major β-secretase, a membrane-bound protease that belongs to the pepsin family of aspartyl proteases [12-14]. Aβ generation is abolished in cultures of BACE1-deficient embryonic cortical neurons [15] and in BACE1 knock-out mice [16,17]. Whereas Luo and Roberdset al. [16,17] reported a normal phenotype of BACE1-deficient mice, more recent studies found severe phenotypic abnormalities in BACE1 knock-out mice [18], challenging BACE1 as safe drug target for AD. Furthermore, additional BACE1 substrates have been reported, suggesting a variety of BACE1 physiological functions. Identified substrates include proteins with important neuronal function, like the β2-subunit of the voltage-gated sodium channel (Navβ2) [19,20], important for normal action potential regulation and neuronal excitability, and neuregulin-1 [21,22], as ligand for members of the ErbB family of receptor-tyrosine kinases, involved in synapse formation, myelination of central and peripheral axons and the regulation of neurotransmitter expression and function [23,24]. Recently, Kim et al. [25] reported that endogenous BACE1 activity also regulates total and surface levels of voltage-gated sodium channels in mouse brains, which also suggests that therapeutic inhibition of BACE1 activity may affect neuronal membrane excitability in AD patients. Notably, soluble β-secreted APP (sAPPβ), representing the N-terminal domain of APP that is cleaved off by BACE1, has been shown to function as a death receptor 6 ligand and mediates axonal pruning and neuronal cell death [26].

BACE1 is highly expressed in neurons, whereas the homolog BACE2 is expressed at very low levels in most brain regions [27] and has not the same cleavage activity on APP as BACE1 [28], emphasizing that BACE1 is the primary β-secretase. However, a potential contribution of BACE2 in amyloidogenic processing and AD pathogenesis cannot be excluded. BACE1 requires an acidic environment for optimal enzyme activity and is therefore mainly found in intracellular compartments with a low pH like endosomes and late Golgi-compartments [13,29,30]. Additionally, BACE1 can be found at the cell surface [13,29,31,32] and recycles between the cell surface and endosomal compartments [29,31]. Beside BACE1 and BACE2, cathepsin B is discussed as an additional β-secretase as inhibition of cathepsin B has been found to reduce Aβ production [33,34]. However, recent findings also implicate cathepsin B as an Aβdegrading enzyme in respect of AD [35,36].

Figure 1:Proteolytic processing of APP. The amyloid precursor protein (APP), a type-I transmembrane protein, can be cleaved in an amyloidogenic and a non-amyloidogenic pathway. The amyloidogenic pathway is initiated by β-secretase (BACE1) cleavage of APP within its extracellular/luminal domain, generating soluble β-secreted APP (sAPPβ) and a C-terminal membrane-bound fragment of 99 amino acid residues, βCTF/C99. βCTF/C99 is further cleaved by γ-secretase, a heterotetrameric protein complex consisting of at least four proteins, PS1 or PS2, Aph1a or Aph1b, nicastrin (Nct) and PEN2. The initial cut by β-secretase BACE1 generates the N-terminus of Aβ, whereas the final cut of βCTF/C99 by γ-secretase generates the C-terminus of Aβ, thus releasing Aβ peptides. In the non-amyloidogenic pathway APP is first cleaved by α-secretases, identified as members of the ADAM family (a disintegrin and metalloproteinase) (ADAM10/ADAM17). Processing by α-secretase generates soluble α-secreted APP (sAPPα) and a C-terminal membrane-bound fragment of 83 amino acid residues, αCTF/C83, which is further cleaved by the γ-secretase complex to generate the peptide p3. The α-secretase cleaves APP within the Aβ domain, thus precluding the formation of Aβ peptides. The γ-secretase cleavage of βCTF/C99 and αCTF/C83 liberates the APP intracellular domain (AICD), which translocates to the nucleus and regulates gene expression [306-310].

BACE1 cleaves APP at the known β-sites Asp1 and Glu11 of the Aβdomain, generating C-terminal membrane-embedded fragments of 99 or 89 amino acids (C99 and C89, respectively) [13,37]. C99 and C89 are subsequently cleaved by γ-secretase within the transmembrane domain, yielding mainly in Aβ1-40/1-42 and Aβ11-40/11-42 [38-41]. Due to the two additional amino acids isoleucine and alanine, Aβ42 peptides are more hydrophobic and aggregate more readily than Aβ40 peptides. Both peptides, full-length Aβand N-terminal truncated Aβpeptides can be found in amyloid plaques of AD brains. Beside the production of Aβ40, which represents with 80-90% of Aβ generated the most abundant species, and Aβ42 peptides, which represent only about 10% of Aβ peptides, additional Aβ isoforms varying in length at the C-terminus of Aβ are released by γ-cleavage [42-44]. The relative unspecificity of γ-secretase might be caused by the unusual intramembrane proteolytic activity of γ-secretase, cleaving APP within the hydrophobic transmembrane domain [45]. The generation of Aβ46 and Aβ49 peptides, also known as ζ-site [46,47] and ε-site cleavage of APP [48,49], suggests as one γ-secretase cleavage model a sequential cleavage of γ-secretase, where cleavage at the ε-site is followed by the ζ-site and finally the γ-cleavage site.

Molecular identification of the γ-secretase has shown that γ-secretase activity resides in a heterotetrameric protein complex. Members of the γ-secretase complex are presenilin1 (PS1) or presenilin 2 (PS2), anterior pharynx defective 1 (APH-1), presenilin enhancer 2 (PEN-2) and nicastrin (NCT) [50,51]. Notably, all components of the γ-secretase complex are, like the substrate APP itself, transmembrane proteins. The assembly of the four components of the γ-secretase leads to the auto- and endoproteolysis of PS into a Nand C-terminal fragment that contribute aspartate residues as active site of the multimeric protease [52-54]. Although all four γ-secretase components are necessary for enzymatic activity, major impact regarding AD pathogenesis belongs to the presenilins. More than 150 autosomal dominant point mutations in the presenilins have been identified, causing familiar early-onset form of AD (FAD) [55,56]. These mutations elevate the generation of Aβ42 peptides [57,58].

Amyloidogenic APP processing by β- and γ-secretase is discussed to be dependent on particular membrane microdomains, called lipid rafts. Lipid rafts are small (10-200nm) dynamic membrane microdomains enriched in cholesterol and sphingolipids.

They are distinct from surrounding non-raft membrane microdomains of unsaturated phospholipids and serve as a platform for diverse cellular processes like signal transduction, cell adhesion and protein trafficking. Lipid rafts are first ensembled in the Golgiapparatus and are highly abundant at the plasmamembrane and the endocytotic pathway. All four members of the heterotetrameric γ-secretase complex as well as BACE1 have been found in lipid raft membrane microdomains [59-61]. Further indications to raftassociated amyloidogenic APP processing are the accumulation of APP C-terminal fragments in lipid raft membrane microdomains in absence of γ-secretase activity [59] and the influence of cholesterol depletion on β- and γ-secretase processing of APP. Cholesterol depletion causes the dissociation of the γ-secretase components from lipid rafts [59] and decreases in general Aβ generation [62-68]. Beside cholesterol, which is important for stabilizing lipid raft membrane microdomains, further lipids have been shown to modulate amyloidogenic APP processing [69-75], indicating that a delicate balance in lipid composition of cellular membranes is crucial for AD pathogenesis. In particular sphingolipids like gangliosides, which are beside cholesterol enriched in raft membrane microdomains, have been implicated in Aβ toxicity. GM1 has been shown to increase Aβ generation [76] and the importance of ganglioside clusters in amyloid fibril formation is of increasing interest. In 1995, Yanagisawa et al. [77] reported that GM1 binds to membrane-bound Aβ (GAβ) which might act as a seed for Aβ aggregation in amyloid plaques [78,79]. Up to date, evidence has increased that binding of gangliosides to Aβ induces a conformational change of Aβ [80-84], which facilitates amyloid fibril formation [85] in the brain. Further studies revealed that the generation of GAβ and the formation of amyloid fibrils preferably occurs in specific membrane microdomains with a lipid raft like composition of sphingomyelin, cholesterol and ganglioside GM1 [86,87]. Notably, the extent of amyloid fibril formation does not only depend on the ganglioside level but is also dependent on cholesterol. Cholesterol has been shown to facilitate the formation of ganglioside clusters important for GAβformation [87] and cholesterol depletion by methyl-β-cyclodextrin, which disrupts lipid raft membrane microdomains, resulted in reduced amyloid fibril formation [88], emphasizing the importance of lipid rafts not only in Aβ generation by β- and γ-secretase but also on the formation of toxic amyloid fibrils.

Similar to the therapeutic inhibition of BACE1 activity, inhibition of the γ-secretase activity to prevent Aβ generation, is not suitable to treat or prevent AD. The γ-secretase complex is beside APP essential for the proteolysis of many type-I transmembrane proteins, for example Notch, ErbB4, CD44, LRP1 and jagged, which exert important functions in normal cellular physiology [89,90]. Therefore a modulation of γ-secretase activity instead of inhibition might be more beneficial to prevent AD or at least to delay the age of disease onset [69,73,75,76].

Non-amyloidogenic APP processing

Beside β-secretase cleavage of APP, APP can be first cleaved by α-secretases in a non-amyloidogenic pathway, thus preventing the generation of Aβ peptides (Figure 1). The α-secretases are members of the ADAM family (a disintegrin and metalloproteinase) and cleave APP within the Aβ domain, generating α-secreted APP (sAPPα) and the C-terminal fragment αCTF, which is cleaved by the γ-secretase complex to generate p3 [38,91-94]. The p3 peptides are not amyloidogenic and sAPPα has neuroprotective and memory enhancing effects [95-97]. α-Secretase processing of APP occurs constitutively (constitutive α-secretase), however additionally α-secretase proteolytic activity can be stimulated by a heterogeneous group of molecules (regulated α-secretase) [98-102]. ADAM proteases are type-I integral membrane proteins of the metzincin family requiring zinc ions for their proteolytic activity [103,104]. So far three members of the ADAM family have been suggested as α-secretases, ADAM9, ADAM10 and ADAM17. ADAM17, also known as TACE (tumor necrosis factor-α converting enzyme), was initially identified as protease responsible for the release of the inflammatory cytokine tumor necrosis factor-α (TNF-α) [105,106]. Several studies implicate ADAM17 in regulated α-cleavage: Fibroblasts of ADAM17/TACE knock-out mice are defective in their protein kinase C stimulated sAPPα secretion [107] and inhibition of ADAM17/TACE in primary neurons leads to the suppression of regulated but not constitutive α-secretase activity [108]. Similarly ADAM9 seems to be involved only in regulated α-cleavage. Phorbol ester treatment promoted sAPPα secretion in COS cells expressing ADAM9 and APP [93], whereas RNAi mediated silnecing of ADAM9 had no effect on constitutive sAPPα generation [109]. Overexpression of ADAM10 in human embryonic kidney cells 293 resulted in the elevation of constitutive and PKC-regulated α-cleavage of APP [92]. However, two recent studies identified ADAM10 to be the constitutive α-secretase in primary neurons [109,110]. RNAi mediated knock-down of ADAM10, but not of ADAM9 or ADAM17, completely suppressed APP α-secretase cleavage in different cell lines and in primary murine neurons [109]. Moreover, ADAM9 or ADAM17 were not able to compensate for this loss of constitutive α-secretase cleavage [109]. Primary neurons of ADAM10 conditional knock-out mice showed reduced α-secretase processing of APP, further demonstrating that ADAM10 represents the most important APP α-secretase in brain [110]. As the non-amyloidogenic processing of APP by α-secretase prevents the formation of amyloidogenic Aβ peptides, an increase in α-secretase activity is an attractive target for the treatment of AD. A further mechanism to modulate Aβ generation might be a shift of amyloidogenic APP processing to non-amyloidogenic processing of APP. The omega-3 fatty acid docosahexaenoic acid (DHA), enriched in marine fish and algae, has been recently described to decrease Aβgeneration in vitro and to decrease amyloid burden in animal models of AD [111-117] via pleiotropic mechanism, including a shift from amyloidogenic to non-amyloidogenic APP processing [73]. Alterations in dietary intake or functional foods might therefore be beneficial for preventing or treating AD [118-120].

Aβ Toxicity

Amyloid plaques consisting of aggregated Aβ peptides are the indisputable characteristic feature of AD, however increasing evidence suggests that small oligomers of Aβ up to 50 Aβ subunits represent the most toxic species of Aβ [121,122]. Up to date several mechanisms of Aβ toxicity have been described, including disruption of calcium homeostasis, cholinergic dysfunction, inflammation, increased oxidative stress and mitochondrial dysfunction (Figure 2) [123-127].

Disruption of calcium homeostasis

Intracellular Ca²⁺ signalling is fundamental to neuronal function and viability. Because of the ubiquitious involvement of Ca²⁺ in second-messenger signalling, neurons at rest have strict mechanisms to maintain low Ca²⁺ concentrations in the cytosol by extruding Ca²⁺ into the extracellular space and pumping Ca²⁺ into the endoplasmic reticulum [128]. Upon activation, Ca²⁺ can flux through voltage-, ligand- or store-operated-channels from the extracellular space into the cytosol or G-protein coupled receptors are stimulated, increasing the generation of inositol-1,4,5-trisphosphate (IP3), which binds to IP3 receptors (IP3R) on the endoplasmic reticulum (ER) to release Ca²⁺ out of the ER into the cytosol. Elevated cytosolic Ca²⁺ level trigger neuronal cellular signalling cascades involved in membrane excitability, neurotransmitter release, gene expression, cellular growth, differentiation, free radical species formation and cell death [129].

Aβ induced Ca²⁺ dyshomeostasis is an important component of AD pathology, altering neurotransmitter receptor properties, disrupting membrane integrity and intitiating apoptotic signalling cascades finally resulting in synaptic degeneration, cell death and devastating memory loss. Aβ has been shown to interact with different Ca²⁺-permeable channels [130] and to increase Ca²⁺ entry into the cytosol. Voltage-gated plasmalemmal Ca²⁺ channels are a major source of cytosolic Ca²⁺ entry in neurons. Aβ significantly increases Ca²⁺ influx via activation of voltage-gated Ca²⁺ channels (VGCCs) of the L-, N- and P-type [130,131], resulting in elevated postsynaptic responses. Beside VGCCs, the Ca²⁺-permeable receptors of the cholinergic and glutamatergic neurotransmitter system, the AMPA and NMDA receptors, are discussed to be involved in AD pathology. These receptors are expressed in brain regions supporting higher cognitive functions, the hippocampus and neocortex, and these brain areas are primarily affected by the neuronal loss observed in AD [132,133]. Aβ oligomers have been shown to modulate NMDA receptor activity [134-136] and to increase NMDA receptor mediated Ca²⁺ influx [137,138], causing dynamin-1 degradation and promoting calpain activity [137] important for synaptic vesicle formation and synaptic vesicle function. However, it has also been reported that Aβ oligomers reduce NMDA-receptor expression and therefore Ca²⁺ influx [139,140].

Cholinergic dysfunction

The malfunction of synaptic integrity is also a consequence of a deregulation in the Ca²⁺-permeable n-acetylcholine-receptor (nAChR) channels. The most vulnerable neurons in AD are discussed to be those expressing high levels of nAChRs, particularly those containing the α7 subunit [141]. Aβ has been shown to bind to α7- andα4β2-nAChRs in cortical and hippocampal synaptic membrane preparations [142] and to affect nAChR functioning [143]. Furthermore, α7- and α4β2- nACHRs positively correlate with neurons that accumulate Aβ [142] and α7-nAChR colocalizes with amyloid plaques [144]. The dramatic degeneration of cholinergic neurons in AD and the loss of cholinergic neurotransmission contributes to cognitive deterioration in AD [145] and led to the development of pharmaceutical drugs targeting cholinergic molecular components, mainly the breakdown of acetylcholine by acetylcholine-esterase [146].

Figure 2:Molecular mechanisms of A�?�? toxicity. Overview of the molecular mechanisms of A�?�? toxicity leading to reduced neuronal function and viability, synaptic degeneration, cell death and devastating memory loss.

Beside Aβ induced alterations in Ca²⁺-permeable plasmalemmal channels or receptors, Aβ influences Ca²⁺ efflux from the endoplasmic reticulum, the most important intracellular Ca²⁺ reservoir. Ca²⁺ can be released out of the ER into the cytosol either by IP3-receptors or ryanodine receptors. Aβ has been shown to stimulate IP3-mediated calcium release from the ER [147] and to increase the expression of G-protein coupled metabotropic glutamate receptor 5, which generates IP3 resulting in Ca²⁺ release out of the ER [148]. An Aβ induced activation of ryanodine receptors (RyR) has been reported for RyR1 reconstituted in planar lipid bilayers [149] and Aβ42 has been shown to increase the expression of RyR3 [150]. Interestingly, several studies have also linked familial PS mutations, increasing the ratio of Aβ42 to Aβ40 peptides, with elevated Ca²⁺ release out of the ER [151-154].

Altered Ca²⁺ homeostasis in AD affected neurons may also be a consequence of the formation of calcium permeable Aβ channels: Aβ peptides incorporate in the lipid bilayer and reorganize to form cation conducting channels in vitro and in intact neurons [155-163]. Recently, the presence of Aβ pores in the cell membrane of post mortem brains of individuals affected by AD but not in healthy individuals have been detected using high resolution transmission electron micoscropy [164]. Furthermore, Diaz et al. [165] reported that blocking Aβ channels by the use of amphiphilic pyridinium salts protect neurons from Aβ neurotoxicity [165].

Decreased membrane integrity

A similar unspecific flux of cations in neuronal plasma membranes is achieved by Aβ induced disruption of membrane lipid integrity. Aβpeptides does not only interact with gangliosides as discussed above, but rather with further membrane lipids like phosphatidylcholine, phosphatidylglycerol and phosphoinositides [166-170], resulting in changed membrane fluidity, discussed to increase membrane permeability to Ca²⁺, Na+ and K+ ions [80,171]. Interestingly, it has also been reported that lack of PS1/2 results in a decreased membrane fluidity [172]. Independent of the mechanism how Aβ causes Ca²⁺ dyshomeostasis in AD, the disruption of intracellular Ca²⁺ signalling finally results in synaptic breakdown, cell death and devastating memory loss.

Increased oxidative stress and mitochondrial dysfunction

Beside influencing neurotransmitter receptor properties and triggering apoptosis [173], destabilization of cytosolic Ca²⁺ levels increases the formation of reactive oxidative species (ROS), resulting in lipid peroxidation and the oxidation of proteins [174,175]. An increase in cytosolic Ca²⁺ level can cause excessive Ca²⁺ flux into mitochondria and increase the production of ROS. In line, Manczak et al. [176] reported mitochondria to be a direct site for Aβ accumulation in AD neurons. Analyzing transgenic mouse models and neuronal cell cultures, Aβ has been found to accumulate in mitochondria, resulting in elevated hydrogen peroxide production and decreased cytochrome-c oxidase activity, leading to mitochondrial oxidative damage, mitochondrial dysfunction and reduced energy metabolism [176], and cell death. Importantly, it is well established that in return oxidative stress itself increases the generation of Aβ [177- 180], emphasizing oxidative stress to be an important factor in the pathogenesis of AD.

Neuroinflammation

Aβ induced activation of immunocompetent cells (microglia and astrocytes) of the brain, leading to neuroinflammation is a further mechanism of Aβ neurotoxicity. Aβ has been shown to activate microglia, however the exact mechanism of Aβ induced microglia activation has not been clearly defined [181]. The involvement of p38 mitogen-activated protein kinase (p38 MAPK), pattern recognition receptors and the toll-like receptors (TLR) in Aβ activated microglia immune response have been discussed [182-184]. Quite recently, Kauppinen et al. [185] reported that the nuclear enzyme poly (ADPribose)- 1 (PARP-1) regulates microglial activation in response to Aβ Injection of Aβ 42 into wildtype mouse brain revealed microglial response, which was blocked in mice lacking PARP- 1 expression. Using microglial cultures they could further show that PARP-1 activity is essential for Aβ-induced NF-κB activation, morphological transformation, nitric oxide release (NO), tumour necrosis factor-α (TNF-α release and neurotoxicity. Treatment of astrocytes with oligomeric Aβ increased the generation of the major pro-inflammatory cytokine interleukin-1 (IL-1), NO and TNF-α in rat astrocyte cultures and lead to increased astrocyte-mediated inflammation [186]. Furthermore oligomeric Aβ correlates with neuronal loss and astrocyte inflammatory response in APP/Tau transgenic mice [187] and astrocytes are important mediators of Aβ- induced neurotoxicity and tau phosphorylation in primary cultures [188]. Similar to the feed-forward cycle that Aβ induces oxidative stress and increased oxidative stress itself elevates Aβ generation, Aβ triggers neuroinflammation, which in turn increases Aβ generation [189-191]. Moreover, oxidative stress leads to the release of proinflammatory cytokine, chemokines and complements, resulting in the activation of microglia and astrocytes [192,193], emphasizing that the described mechanisms of Aβ toxicity gear into each other and that AD is a multifactorial neurodegenerative disease.

Notch and Alzheimer’s Disease

The Notch signalling pathway is also discussed to be implicated in the pathogenesis of AD. Notch receptors are type-I transmembrane proteins, which are processed in a similar way to APP (Figure 3). During its maturation in the secretory pathway, the Notch receptor is constitutively cleaved at the S1 site by a furin-like protease, generating a heterodimeric molecule, which consists of an extracellular and a transmembrane fragment, remaining non-covalently associated [194]. Binding of DSL ligands (Delta/Serrate/LAG-2) of adjacent cells to cell surface localized Notch receptors induces cleavage of Notch at the S2 site. In analogy to α-secretase cleavage of APP, S2 cleavage of Notch is mediated by proteases of the ADAM family [195-198] and is located in the extracellular domain of Notch close to the transmembrane domain. The membrane-embedded remaining Notch fragment NEXT (Notch extracellular truncation) is further processed at the S3 site by the γ-secretase complex [199-201], generating the Notch intracellular fragment (NICD), which translocates to the nucleus, where it participates directly in the transcriptional regulation of target genes by interacting with DNA-binding proteins of the CSL-family (mammalian CBF-1/Drosophila Su(H)/C. elegans LAG-1) [202].

Figure 3:Proteolytic processing of Notch. During its maturation in the secretory pathway, the Notch receptor is constitutively cleaved at the S1 site by a furin-like protease, generating a non-covalently associated heterodimeric molecule. Upon activation of the Notch signalling pathway by binding of DSL ligands to cell surface localized Notch receptors, the heterodimeric Notch molecule is cleaved at the S2 site. In analogy to α-secretase cleavage of APP, S2 cleavage of Notch is mediated by proteases of the ADAM family. The membrane-embedded remaining Notch fragment NEXT (Notch extracellular truncation) is further processed at the S3 site by the γ-secretase complex, generating the Notch intracellular fragment (NICD), which translocates to the nucleus, where it participates directly in the transcriptional regulation of target genes involved in the generation, differentiation and survival of neuronal cells.

The Notch signalling pathway is a highly conserved signalling system in multicellular eukaryotes, regulating cell-fate specification and differentiation processes during development, including neuronal development [203-204]. Beside its critical role in neuronal development, the Notch signalling pathway also functions in the adult brain [205], controlling neural stem cell maintenance, morphology, migration, synaptic plasticity and survival of immature and mature neurons and long-term memory related to cognitive function [206-209]. Dysregulated Notch signalling has been implicated in many diseases, e.g. cancer [210,211], CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) [212], Allagile [213,214], Hajdu-Cheney syndromes [215,216], multiple sclerosis [217] and Down syndrome [218]. Several indices argue for a potential role of the Notch signalling pathway in AD: Notch is expressed at particularly high levels in the hippocampus of adult brains [219], one of the brain regions affected by AD; Notch plays a role in learning and memory [220] and Notch is a substrate of the γ-secretase complex, which is also involved in the generation of amyloid plaques [221]. Notch1 expression has been shown to be elevated more than 2-fold in the hippocampus of sporadic AD patients compared to control human hippocampus [219]. Furthermore, Notch1 colocalizes and interacts with PS1 [219,222] and APP [223]. The APP intracellular domain (AICD), which is like NICD released by γ-secretase proteolytic activity, has been reported to bind to Numb-proteins, known cytosolic Notch inhibitors, and to repress Notch/NICD activity [224]. This study suggests that γ-secretase has opposing effects on Notch signalling, positive by cleavage of Notch at the S3 site and the resulting generation of NICD, which translocates to the nucleus and activates transcription of genes involved in the generation, differentiation and survival of neuronal cells and negative by γ-secretase processing of APP, generating AICD, which inhibits NICD function [224]. The inhibition of Notch function by AICD might accelerate the neurodegenerative process of AD by enhancing synapse loss, neurite dystrophy and neuronal degeneration. Moreover, for FAD linked PS1 mutations inefficient processing of the Notch receptor has been recently reported to be responsible for impaired self-renewal and differentiation of adult brain neural progenitor cells [225], further indicating that alterations in the Notch signalling pathway may contribute to the pathogenesis of AD.

Tau Hallmark

Beside amyloid plaques, neurofibrillary tangles are considered to be a pivotal pathological hallmark of AD. Neurofibrillary tangles (NFTs) consist of insoluble paired helical fragments (PHF) inside neurons composed mainly of hyperphosphorylated tau protein [226- 229]. Tau proteins are mainly expressed in neurons and can be found in axons [230] and the somato-dendritic compartment [231]. They belong to the family of microtubule-associated proteins (MAPs), important for the assembly of tubulin monomers into microtubules, to stabilize the neuronal microtubule network which is essential for maintaining cell shape and axonal transport [232]. Tau is a phosphoprotein and is found in six isoforms in human brain [233]. The microtubule assembly promoting activity of tau, the major MAP of a mature neuron, and the other two neuronal MAPs (MAP1 and MAP2) is regulated by their phosphorylation status [234,235]. In AD tau proteins are hyperphosphorylated and polymerize into paired helical fragments forming intraneuronal neurofibrillary tangles [226]. Tau pathology is not limited to AD but is also present in other dementing disorders like Pick’s disease, progressive supranuclear palsy and corticobasal degeneration [236,237]. However, the morphology of the NFTs and the composition of the tau isoforms differ from those of AD [238].

The degree of tau phosporylation and therefore tau function is regulated by protein kinases and protein phosphatases. So far, 79 potential serine and threonine phosphorylation sites in tau have been described [239-241] and the abnormal hyperphosphorylation as observed in AD is discussed to be caused either by activation of protein kinases or by reduced activity of protein phosphatases.

Protein kinases involved in tau phosphorylation

Glycogen synthase kinase-3β (GSK3β) has been found to be one of the most important kinases responsible for tau hyperphosphorylation [242-244] and promotes tangle-like filament morphology [245]. Overexpression of GSK3β in cultured cells and in transgenic mice [246,247] leads to tau hyperphosphorylation and GSK3β inhibition by lithium chloride reduces tau phosphorylation [248,249]. Beside GSK3β, casein kinase 1 delta, protein kinase A and the calcium and calmodulin dependent protein kinase-II (CaMKII) have been found to phosphorylate phosphorylation sites which are also phosphorylated in tau proteins present in PHFs in AD [250-253]. A further important candidate involved in tau phosphorylation is the cyclin-dependent kinase 5 (CDK5). Besides GSK3β, CDK5 is highly expressed in human brain [254,256] and both kinases have been shown to be associated with all stages of neurofibrillary changes in AD [257,258]. Silencing of CDK5 reduces the phosphorylation of tau in vitro (neuronal cell cultures) and in vivo (wildtype mice) and knock-down of CDK5 strongly decreased the formation of NFTs in hippocampi of triple transgenic AD mice [259]. Overexpression of p25, a cellular activator of CDK5, in primary neurons and in transgenic mice results in tau hyperphosphorylation and tau aggregation and neurofibrillary pathology in mice [260-262]. Mitogen-activated protein (MAP) kinases, including ERK1, ERK2 [263,264], p70S6 kinase [265] and the stress-activated kinases JNK and p38 kinase [266-268], have been shown to be also involved in tau hyperphosphorylation. Recently, the dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) has been shown to phosphorylate tau at several phosphorylation sites [269,270]. Notably, tau phosphorylation by Dyrk1A primes tau for further phosphorylation by GSK3β [269].

Protein phosphatases involved in tau dephosphorylation

Several protein phosphatases (PPs), including PP1, PP2A, PP2B and PP5 have been proposed to be involved in tau dephosphorylation in vitro and in vivo [271]. However, PP-2A and PP-1 contribute more than 90% of the serine/threonine protein phosphatase activity in mammalian [272]. PP2A is discussed to be the main enzyme that prevents hyperphosphorylation of tau. Decreased PP2A mRNA expression and reduced PP2A activity have been detected in brains of AD affected individuals [273,274]. PP2A also regulates the activities of several tau kinases, including ERK1, ERK2, p70S6 kinase, CaM Kinase II and PKA. Reduced PP2A activity as observed in AD brain promotes tau phosphorylation by these kinases, emphasizing the role of PP2A in AD by directly decreasing tau dephosphorylation and indirectly by promoting tau phosphorylation. Beside PP2A, which has been show to be reduced in AD brain, the activity of protein phosphatase PP1 has been also shown to be reduced in AD brain [271,274,275], emphasizing the impact of PP2A and PP1 in neurofibrillary changes in AD.

Quite recently, a further protein, early growth response 1 (Egr-1), was described to be involved in tau pathology. Egr-1 is a transcription factor significantly upregulated in AD brain [276,277]. Lu et al. [278] recently identified the pathological significance of this upregulation. Overexpression of Egr-1 controls both, phosphorylation and dephosphorylation of tau, by activating CDK5 and inactivating PP1, leading to tau hyperphosphorylation and destabilized microtubules.

Tau toxicity

Beside polymerization of hyperphosphorylated tau in neurofibrillary tangles, hyperphosphorylated tau might cause conformational changes [279,280] and cleavage of tau by caspases [281,282]. Truncated tau is discussed to be a more favorable substrate for abnormal hyperphosphorylation as truncated tau promotes tau hyperphosphorylation and neurofibrillary degeneration in vivo in transgenic rats [283]. Furthermore, hyperphosphorylated tau is resistant to degradation by calpains [284,285], calcium activated neutral proteases and the proteasome [286], indicating that increased tau level observed in AD brain [287] are caused by a decrease in its turnover.

In the axons, non-fibrillized hyperphosphorylated tau is discussed to disrupt microtubules by sequestering normal tau and the two other neuronal MAPs, MAP1 and MAP2, whereas its aggregation as neurofibrillary tangles probably impairs axoplasmic flow and leads to slow progressive retrograde degeneration and loss of connectivity of the affected neurons [288]. In the somato-dendritic compartment hyperphosphorylated tau has been found to influence intracellular compartments by inducing fragmentation of the Golgi apparatus and by reducing mitochondria and rough endoplasmic reticulum [289,290]. The accumulation of hyperphosphorylated tau in the ER might cause neurodegeneration due to prolonged ER stress [288,291].

Linking Tau and Amyloid Pathology

Although Aβ and tau exert their neurotoxic effects through separate mechnisms, several in vitro and in vivo studies suggest a link between Aβ and tau pathology. As described tau pathology is caused by the hyperphosphorylation of tau, which is regulated by kinases and phosphatases. Aβ has been shown to activate GSK3β, one of the main kinases involved in tau phosphorylation, leading to aggravated tau pathology in the hippocampus and cortex of a transgenic mouse model, expressing mutant APP and mutant tau [292]. Furthermore, mutations in PS increased GSK3 activity and tau hyperphosphorylation in cell culture experiments [293]. More recent studies revealed that double transgenic mice, expressing mutant tau and mutant APP showed enhanced neurofibrillary tangle pathology in the limbic system and olfactory cortex compared to mice expressing solely mutant tau [294] and that intracranial injection of synthetic Aβ42 accelerates neurofibrillary tangle formation in mutant tau transgenic mice [295]. In return, immunization against Aβ revealed reduced levels of hyperphosphorylated tau in triple transgenic mice [296]. However, the causal link between aberrant APP processing and tau pathology in AD remains controversial as double transgenic mice expressing mutant APP and mutant tau show enhanced amyloid deposition compared to single transgenic mice [297]. Furthermore, knock-out of tau protects neurons from Aβ-induced cell death [298-300]. One of these studies implicated NMDA-receptors to be involved in reduced Aβ neurotoxicity [299]. As described above, Aβ is discussed to exert its toxic effect via alteration in NMDA-receptor function. Ittner et al. [299] recently described that tau is responsible for postsynaptic targeting of the src-kinase Fyn, which phosphorylates NMDA-receptors. Reduced dendritic localization of Fyn in animals lacking tau resulted in reduced interaction of NMDRs with PSD95 and as a consequence reduced Aβ-mediated excitotoxicity [299], suggesting that tau-dependent dendritic signalling is crucial for mediating Aβ neurotoxicity.

Further research regarding the cellular function of tau proteins and especially APP [66,301-305] is necessary to understand the link between tau and amyloid pathology and to further identify the mechanism involved in the development of AD.

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