Tau and Neuron Aging

Abstract

Tau protein could appear like a family of multiple isoforms rising by alternative splicing of its nuclear RNA or by different posttranslational modifications. The levels (or proportion) of these different tau isoforms could change in different neurons during development, aging or disease (tauopathies) in mammals. It is discussed that in some disorders there is a gain of toxic function of modified tau, due to the phosphorylation or aggregation of tau protein. These phenotypic changes are mainly found in aging organisms. On the other hand, loss of tau function could facilitate the appearance of some defects (related to iron toxicity) in aging animals lacking tau.

Tau is a microtubule associated protein mainly present in neurons. There is a unique human tau gene located on chromosome 17 [1]. The chromosome loci17q 21.31, where gene tau is present, contains a common inversion polymorphim of around 900kb. It results in the presence of two different haplotypes for tau gene (MAPT). These haplotypes are known like H1 and H2 haplotypes. The first, H1, haplotype is associated with an increased expression of tau protein. Thus, an important feature about tau genetics is the presence of these two haplotypes, H1 and H2, in which there is an inversion of a segment, containing tau gene, in H2 chromosome with respect to its H1 counterpart [2]. Also, copy number variations affecting tau gene involving partial deletion and complete duplication of the gene have been described [3].

Tau gene is transcribed into nuclear RNA. This nuclear RNA yields different mRNA species by alternative splicing to generate a protein family of different tau isoforms containing different number of exons [4]. In the central nervous system, there are different tau isofoms containing or lacking exons 2, 3 and 10 [5]. Mainly, the characteristics of those tau isoforms containing or lacking exon 10 have been compared, because exon 10 encodes for one of the tau regions involved in the binding of tau to microtubules. Indeed, there is a cluster, in tau protein, of four microtubule binding regions containing similar but not identical sequences of 31 or 32 residues [6] and the third one of them is encoded by exon 10 (Figure 1). Thus, depending on the presence or absence of exon 10, there is a tau isoform containing four (tau 4R) or three (tau 3R) microtubule binding regions, being the binding of tau 4R to microtubules stronger than that of tau 3R.

Figure 1.

Scheme of tau molecule. Upper part is showing the longest central nervous system human tau isoform. In gray, the presence of two exons (2 and 3) is indicated and, in black, that of the four similar, but not identical (R1 to R4) tubulin binding regions. Lower part shows tau molecule divided in four parts. (A) Indicates the most variable parte of the molecule, when tau molecules from different organism are compared. (B) Shows a proline rich region that could be highly modified by phosphorylation. (C) Indicates the tubulin binding region. (D) Shows the C-terminal region that could be also modified by phosphorylation, at several residues. Inset shows the shortest and longest human tau isoforms. The first is mainly present in fetal (F) brain whereas the second is present in adult (A) brain.

In this review, we will comment on the function of tau isoforms and their modification during aging or disease.

Tau function

In the first studies, tau was discovered as a microtubule associated protein and by analysis in vitro, or in cultured cells, it was described that tau facilitates tubulin assembly into microtubules [7]; that tau stabilizes polymerized microtubules [8–10]; or that tau could suppress microtubule dynamics [11]. Also, tau binding to microtubules appears to be through its interaction with protofilaments and, recently, has been suggested that tau protein could diffuse along the microtubule lattice [12]. Tau protein shares some of these features with other microtubule associated proteins (MAPs). However, there are some specific differences between tau and other MAPs. One of these differences is the appearance of tau during neuron development. Tau is expressed later than other MAPs during development as it appears in the neuron when the developing cell is closed to the time required for maturation and when the newborn neuron is almost ready to contact with other neurons [13].

Other specific functions for tau protein have been suggested. The functions involve the binding of tau to some proteins related to axonal transport [14–16]; the binding of tau to proteins involved in tubulin acetylation [17, 18]. Tau could also bind to dendritic proteins [19], or to mitochondria [20, 21].

To study tau function in a living organism, mice lacking tau have been raised to compare their phenotype with that of wild type (wt) mice [22, 23]. Young mice lacking tau are viable and with a similar phenotype to that of wt mice, showing only minor differences in behavior [24] or gene expression [25]. However, some changes have been found in aged animals (see below). To explain the viability of tau deficient mice, it has been suggested that the lack of some tau functions, like microtubule stability could be compensated, by the presence of other MAPs doing similar functions [22].

Tau in neuron development

As previously indicated, tau is expressed later than other MAPs during neuron development, being fetal tau mainly composed of tau 3R isoforms. Also newborn cells, raised in adult neurogenesis at the dentate gyrus, contain a high proportion of tau 3R isoforms [26]. In addition fetal tau could be highly modified by phosphorylation not only during development [27], but also in adult neurogenesis [28]. Later on, adult neurons contains tau isoforms with exon 10 (tau 4R) and with a lower level of phosphorylation compared to that of fetal tau.

Tau and neuron aging

The age for many of the central nervous neurons of a mammal, like human or mouse is that of the age of the organism. Only there are some few younger neurons that arise in the adult organism in some specific sites, like dentate gyrus, but mainly the majority of neurons aged with their organisms. A consequence of that aging is an increase of neuron vulnerability to oxidative damage, a damage that could result in the appearance of peroxidation products [29] that could modify tau protein [30, 31], a modification that could facilitate tau aggregation [32, 33]. Also during aging, brain changes in mitochondria could take place [34] and it has been described that a mitochondrial protein, DRP1, involved in mitochondrial fission, could abnormally bind to tau, promoting neurodegeneration through mitochondrial dysfunction [21].

Aging is the main risk for several neurodegenerative disorders like Alzheimer or Parkinson disease. In Alzheimer disease (AD) is well known, from long time ago, that there is an increase in the amount of tau, an increase in tau phosphorylation and an increase in tau aggregation in the brain of the patients affected with the disease [35]. It appears that the increase in the amount of tau is not due to an increase in the synthesis of the protein but to an impairment of its degradation by the proteasome or by autophagy pathways [36]. In the process of tau degradation, some heat shock proteins could be involved [37] to coordinate tau homeostasis or function in an isoform specific manner [38]. Recently, it has been suggested that a posttranslational modification, tau acetylation, may also decrease tau degradation because acetylation of some lysine residues in tau molecule could prevent their ubiquitination, a modification that could be required for the degradation of tau via proteasome [39, 40].

In AD tau becomes increasingly phosphorylated at many different sites [41]. This phosphorylation may detach tau from microtubules and facilitate itsself aggregation [42]. Tau could be modified by several kinases and dephosphorylated by several phosphatases [27]. One of the main tau kinases is GSK3, a kinase that could be activated by the presence of beta amyloid peptide, probably in oligomeric form [43–46]. Not only tau phosphorylation could facilitate tau aggregation but also other modification, tau truncation, could induce the aggregation of tau [47, 48]. On the other hand, the possible toxic role of filamentous tau aggregates is under discussion [48].

Intracellular phosphorylated tau could be toxic [49], but also amyloid peptide toxicity could be modulated by tau protein [50–53]. In other neurodegenerative disorders, tauopathies, there is also the presence of phosphotau and tau aggregates that could be toxic for neurons. Different tau aggregates and filaments (paired or straight) could be present in different diseases, raising by different composition of tau isoforms (tau 3R and tau 4R) or by different posttranslational tau modifications [32, 54] in those tau aggregates. Also, the presence of tau mutations could be the primary cause for the onset of some of these diseases [26, 35].

In Parkinson disease, the absence of tau function could contribute to toxic iron accumulation in areas like the substantia nigra. It has been indicated that tau couples with amyloid precursor protein to export iron from neuronal cells [55] and the absence of tau function may result in iron accumulation, an accumulation that could be toxic in old animals.

A consequence of the neuron toxicity in these neurodegenerative disorders is the presence of neuron death and, intracellular tau could be released to the extracellular space where it could be toxic to the surrounding neurons [56].

Toxicity of extracellular tau

Extracellular tau, raised after neuron death, could become toxic after binding to specific cell receptors present in surrounding neurons. These receptors have been identified as the muscarinic M1 and M3 receptors [57, 58]. The result of that interaction of tau with muscarinic receptors is an increase in intracellular calcium [59].

On the other hand, it has been reported that tau spreading from neuron to neuron could take place in the absence of neuron death in an exocytosis-endocytosis manner in cell or animal models [60, 61]. More recently, it has been suggested that tau could be transferred from one neuron to neighboring neurons through synaptic contacts [62, 63]. To study if any of these ways for tau spreading, from neuron to neuron, may take place in humans, a preliminary study based in the analysis of the nature of tau protein, present in cerebrospinal fluid of Alzheimer disease patients was carried out. The result of this analysis showed that uncoated tau (probably arising from neuron death), but also vesicle secreted tau (compatible with the transfer from neuron to neuron through exocytosis and endocytosis) are present in the cerebrospinal fluid of AD patients [64].

In summary, tau protein, the product of a single gene, could yield to the formation of different isoforms by alternative splicing of its nuclear RNA or by posttranslational modifications. The level of these tau isoforms could change during the development, aging or disease in mammals. In this way, aging is the main risk for the onset of several neurodegenerative diseases including some tauopathies, like Alzheimer disease.