Transthyretin (TTR), a carrier protein for thyroxine and retinol present in the plasma and cerebrospinal fluid (CSF), has been shown to sequester the amyloid beta-peptide deposition in the brain   . The transthyretin gene is mainly expressed in the liver and choroid plexus of the brain. Transthyretin plays a very important role in binding and distribution of thyroid hormones in the body and brain to protect it during neurological strokes   . The choroid plexus of the brain secretes TTR at a rate 13 times greater than liver  . The total TTR proteins contents account for at least 20% of all synthesized by the choroid plexus in the rat brain. It has been suggested that uni-directional secretion of TTR proteins to the CSF plays a key role in the transfer of thyroxine (T4) from the blood to the CSF, as TTR may drive thyroxin hormones (TH) across the blood-CSF barrier  . TTR is a major distributor of T4 in the CSF and its distribution from CSF to the brain is dependent on TTR based receptor-mediated endocytosis process    . Although, TTR possesses the higher affinity for thyroxine binding proteins (TGB) than T4, it may only involve in the peripheral circulation. TTR-T4 binding can be seen in the CSF promoting T4 transport from blood to brain  . TTR is also indirectly implicated in the transport of vitamin A through interaction with retinol-binding protein (RBP)  .
Besides its role as a carrier protein, TTR has been involved in the sequestering of β-amyloid peptide (Aβ) in the brain, protecting the brain from neurotoxic accumulations called amyloid plaques. However, it is unclear whether TTR affects the clearance of β-amyloid from the CSF  . In vitro studies showed that TTR via its TGB interacts with Aβ residues, preventing its toxicity in the brain cells     . TTR is suggested to be a protease molecule with apolipoprotein structure A-I (apoA-I) and Aβ as substrates. TTR cleaves Aβ at multiple positions to degrade aggregated forms of Aβ. In vivo studies suggested that TTR can transport Aβ from the brain to blood but not into the brain  . TTR crosses the monolayer of cells only in the brain-to-blood direction. TTR-mediated Aβ clearance is through LRP1, as lower receptor expression was found in brains and livers of TTR knockdown mice and in cells incubated without TTR   . The activated TTR may contribute not only to the upholding of Aβ levels within a normal range but also to the degradation of deposited Aβ in the case of imbalance and diseases condition  .
This review addresses some of the key questions like
1) TTR-A neuroprotective and neurite growth protein.
2) TTR-important contributor in learning and memory.
3) Special role with respect to Alzheimer Disease (AD).
2. Transthyretin Promotes Neurite Outgrowth in Hippocampal Neurons and Provides Neuroprotection
TTR protein has the ability to enhance neurite outgrowth in vitro, plays apivotal role in nerve regeneration process and provides neuroprotection in the peripheral and central nervous system    . In vivo and in-vitro studies showed that, in the absence of TTR, both hippocampal neurite outgrowth and nerve regeneration were impaired   . TTR significantly boosted neurite outgrowth via megalin receptor in hippocampal neurons, both in number and length   . Neuronal cell lines exposed to TTR KO serum displayed 25% decrease in neurite number per cell and in the length of the longest neurite in cell culture, when compared to cells grown with WT culture. To ascertain whether the absence of TTR protein was directly liable for this decreased in neurite number and size, TTR KO serum supplemented with wild type TTR was able to totally rescue the phenotype observed in the absence of the protein  . Several studies pointed that it can be a good predictor for stroke patients exhibiting decreased serum TTR and young women, owing to the neuroprotective action of steroids that are up-regulating TTR     . Familial amyloid polyneuropathy (FAP), a neurodegenerative disorder is caused by TTR deposition in the peripheral nervous system (PNS). The reason for TTR deposition in the nerve leading to FAP is still unknown. When TTR was delivered in TTR knock-out (KO) mice, the sciatic nerve regeneration phenotype was rescued.
TTR binds several different proteins including megalin (LRP-2), RAGE (receptor for advanced glycation end products) and IGF-IR (insulin-like growth factor 1 receptor)      to activate the downstream signaling pathways. These signaling pathways activated by TTR in the CNS lead to neuroprotection under physiological and pathological conditions involving TTR dependent activation of mitogen-activated protein kinase (MAPK), extracellular receptor kinases (ERK1/2) and Akt through Src, leading to the phosphorylation of transcription factor CREB (Figure 1)   . In addition, TTR promotes a transient rise in intracellular calcium through anN-methyl-D-aspartate receptor (also known as the NMDA receptor), in a Src/megalin-dependent manner  . The megalin molecule possesses Src homology domain (SH3) constitutes a crucial point of convergence for signaling pathways. This bridging molecule Src could be responsible for the increase in calcium level inside neurons via activating NMDA receptor because Src regulates NMDA receptor activity    .
The second pathway through which TTR stimulation rescues cell death and neurite loss is by activating Bcl2 protein family members in megalin-dependent manners. TTR stimulation under excitotoxic conditions rescued TTR KO hippocampal neurons in a megalin-dependent manner, which were more sensitive to excitotoxic degeneration than WT neurons  . In this process, TTR activates CREB, contributing to changes in the balance between Bcl2 protein family members, toward anti-apoptotic proteins (Bcl2/BclXL compared to Bax protein)     . TTR triggered by its interaction with a well-known neuroprotective megalin-dependent signaling pathways promotes a robust neurite outgrowth response in hippocampal neurons by the upregulation of intracellular calcium and MAPK pathways (Figure 1). Megalin was identified
Figure 1. TTR via different signaling pathways responsible for phosphorylation and increase of intracellular calcium level lead to promote neurite outgrowth and provides neuroprotection with apoptotic gene under excitotoxic conditions.
as the receptor involved in the transduction of TTR neuroprotection via megalin in hippocampal neuronal cell culture  . TTR interaction with megalin was found to be important determinant for neuronal survival and neurite preservation both in excitotoxic conditions and in a mouse model of permanent middle cerebral artery occlusion (pMCAO). As megalin was necessary for the neuroprotective action of TTR, megalin mRNA levels was quantified after glutamate stimulation in both TTR KO and WT cultures. Megalin mRNA was found to be significantly upregulated in WT cultures in opposition to TTR KO cultures indicating that megalin is required for proper functioning of TTR. TTR up-regulates intracellular calcium and takes Src/ErK/Akt/CREB pathway in a megalin-dependent manner both in vitro and in vivo. Moreover, clathrin-dependent megalin-mediated TTR internalization is required for TTR neurogenic activity in dorsal root ganglia neurons. Supporting this notion, it was demonstrated that megalin’s action as an enhancer of nerve regeneration is dependent on TTR expression and decrease levels of megalin lead to slow down the nerve regeneration process   . Keeping in view the above discussions, TTR might be regarded as a neurotrophic factor, both in neurite outgrowth and neuroprotection under physiological conditions.
3. Role in the Maintenance of Learning and Memory Capacities of Brain
In this section, we ascribed the questions like how TTR regulate learning and memory? Which mechanism is more critical in maintaining it? Does TTR also contribute to play its different role during aging process? To shed light on these aspects, we have tried through a reductionist approach.
Learning and memory is a complex process accompanied by molecular modifications and is driven by hippocampus genes  . To elucidate the molecular mechanisms responsible for stable forms of long-term memory consolidation require the induction of a cascade of genes responsible for producing and maintaining structural changes associated with memory formation. Despite all these molecular changes that are enhancing memory, little is known about molecular events most relevant to recover learning and memory deficit   . Emerging evidence on protein interaction networks that monitor and respond to the normal memory enhancing process suggested that TTR is involved in neurodegenerative disorders like Alzheimer disease  .
The hippocampus, a structure essential for the formation and retrieval of spatial and reference memory, is necessary for long-term memory consolidation or storage    . Genome-wide study investigated genes differentially expressed between aged memory-impaired (AI) and aged memory-unimpaired (AU) rats      . Long-term memory formation depends on two distinct parameters, 1) gene expression and 2) protein synthesis  . TTR is one of the most markedly affected genes between the two groups: aged memory-impaired (AI) and aged memory-unimpaired (AU) rats  . Studies showed that TTR is a critical component of the retinoid pathway for the maintenance of memory capacities during aging      . The upregulation of TTR is essential to prevent from memory deficits. During AI and AU conditions, TTR gene expression was affected most markedly. Decrease TTR gene expression may considerably alter the bioavailability of retinoic acid (RA) in response to the body’s needs because TTR delivers retinol to the target tissue as well  . This could be attributed partially to diminish the activity of C/EBP (a transcription factor regulating both TTR and NQO2 expression) immediate-early gene cascade initiated by CREB since C/EBP protein levels were decreased in AI animals    . Genetic, behavioral studies and molecular evidence supported the notion that TTR is involved in the maintenance of normal cognitive processes during aging by acting on the retinoid signaling pathway   . TTR and RA deficiency in the hippocampus may decrease memory performance by impairing synaptic plasticity  , long-term potentiation (LTP) and long-term depression (LTD)   .
TTR influence learning and spatial memory in a robust way. Studies carried out using TTR knockdown mice demonstrated that it regulate the cognitive process and protect the brain from traumatic injury  . Hippocampus-dependent memory impairment is associated with synaptic dysfunction/alterations that occur during normal aging   . Several lines of studies pointed that TTR accelerates the cognitive decline resulting from aging. Impairment resulting from TTR knockdown gene also temporary proceeds to functional deficits in processes mediated by prefrontal cortex  -  . TTR-null mice showed increase neuropeptide Y levels in the hippocampus  . Over-expression of neuropeptide Y in the hippocampus of transgenic rats induces spatial memory impairment, which could also be interconnected to the cognitive phenotype in TTR knockdown mice  .
Hippocampus 14-3-3ζ proteins are highly conserved acidic proteins representing 1% of the total amount of brain proteins and very important in many cellular processes, being their absence related to memory deficits and learning  . In neurons, this protein exists in the cytoplasm, in mitochondria, and also in the nucleus   . Several studies revealed that TTR regulates 14-3-3ζ protein levels in the hippocampus   . TTR knockdown mice had decreased levels of 14-3-3ζ protein in the hippocampus and this decreased level impact on learning and memory  . The cognitive decline with decreased expression is strongly connected with synaptic activity-dependent proteins  . Western blot and immunohistochemistry analysis described the increase degradation of 14-3-3ζ protein of lysosome in the absence of TTR, increasing autophagy and memory deficits process      . In conclusion, the absence of TTR decreases 14-3-3ζ protein levels in the hippocampus which in turn attributable to increased degradation in the lysosomal compartments, probably by the reduced levels of 14-3-3ζ protein   .
4. TTR Role in Alzheimer Disease
Alzheimer disease is a neurodegenerative disorder primary characterized by the extracellular deposition of Aβ and the formation of neurofibrillary tangles in the brain    . In AD patients, two different mechanisms are involved, overproduction versus accumulation of soluble Aβ  . In both cases, sequestering of Aβ contribute to its clearance from the brain and protect against accumulation or susceptibility to diseases. The TTR plays pivotal role during this process by activating downstream signaling events leading to Aβ sequestering. The hallmark of TTR is its role in Alzheimer’s disease, protecting the brain from accumulating neurotoxic amyloidplaques. TTR suppressed Aβ and prevent its toxicity   . Studies showed that TTR sequestered Aβ in the CSF and moved Aβ to the choroid plexus (CP) for enzymatic degradation and removal from the brain  . In this context, TTR-Aβ interaction seems to have a neuroprotective effect in AD patients    . Brain TTR exhibits asymmetrical expression pattern and was confirmed in normal and transgenic mouse model in AD condition  . The levels of TTR in the brain of AD patients are correlated negatively with the abundance and accumulations of amyloid plaques. In response to elevated Aβ levels, the TTR is up regulated in transgenic mice overexpressing mutant amyloid precursor protein   .
Patients suffering from AD showed significant reduction of TTR concentration in the CSF compared to age-matched healthy control subjects suggesting that AD patients expressed decrease TTR level with an enhanced level of Aβ in the brain (p = 0.004)     . Gene expression of TTR can be induced in response to overproduction of Aβ but this seems to be in contrast to the observations that the concentration of TTR is lower in most cases, if not all, AD patients than in aged-match control groups    . In situ hybridization analysis identified very low level of TTR mRNA transcripts in the hippocampus while the majority was localized in the choroid plexus of the brain  . Results from the experiment using C57BL/6JNarl mice and Tg2576 mice showed that not only the level but also the hemispheric symmetry of TTR expression in the mouse brain was significantly altered in the AD mouse model Tg2576  . Interestingly, in this study, the levels of TTR transcripts in the hemispheres of the adult females, aged females, and aged males were all higher than the adult males. Furthermore, this asymmetrical distribution of TTR in the brain hemispheres might have an important link with the pathogenesis of the AD   .
The implication of TTR as a neuroprotective agent in AD was further validated by two well-characterized models of AD: the APP-V717I and the Tg2576 (K670N, M671L) transgenic mice, described to display cognitive impairment and amyloid plaques    . By immunohistochemistry analysis, TTR immunoreactivity was restricted to the choroid plexus of the brain. These two validated models of AD clearly showed that TTR expression can be seen in choroid plexus and mutation to TTR can lead to disease pathology  .
Oxidative stress and inflammation also contribute to AD. Multiple genes and molecular mechanisms have been implicated in this process. Significantly altered gene expression was found in AD-affected Choroid Plexus Epithelium (CPE)  . Specific cellular changes were observed due to increased oxidative stress. Most likely, CPE sink action may be impaired in AD patients due to down regulation of CLDN5 gene. Aβ PP processing pathways are responsible for AD condition (Figure 2)  . Reduced TTR levels in CSF have also been reported in AD patients with depression. The inconsistency among the finding has made it an unsuitable CSF marker for AD patients and made it more complicated to understand its role in AD pathogenesis. The third way, the TTR affect AD model depends upon its function as an RBP binding protein. Increased TTR indirectly
Figure 2. Amyloid precursor protein (APP) processing pathway during Alzheimer Disease. AICD, AbPP intracellular domain; C83 (C99), carboxy-terminal fragments C83 (C99); DR6, death receptor 6; LRP, lipoprotein receptor-related protein; sAPP, secreted AbPP fragment; TTR, transthyretin. Degradation, see “Clearance of Ab” of the text for details. Involvement of TTR regulation: it has been suggested that APP or its fragments upregulate TTR  .
increases the amount of available retinoic acid in the brain, thus enhancing neuronal maintenance. Similarly, the accelerating effect could also depend on a relative lack of retinoid in the CNS which amplifies Aβ. RBP inhibitors have been shown to compromise neuronal function in aged rodents whereas retinoic acid has been found to enhance performance   .
Despite the stable role of TTR in the CNS and AD, it is far to understood the specific and pivotal role of TTR’s site of synthesis in AD. Altered TTR gene expression in the choroid plexus and the TTR levels in CSF consequently could impact on AD pathology and disease prognosis. Further studies are needed to explore the main domain of TTR in AD so that it can be recovered in a more sophisticated way. The scenario like that could certainly account for the findings in the overexpression models of AD, whether it applies to sporadic disease is a subject matter of speculation and further investigation. Any such studies could not ignore the possible role of TTR since cortical and hippocampal neurons from human AD and mouse AD model brains seem to increase its production  .
TTR plays a significant novel role in sequestering of beta-amyloid peptides deposition in the brain, promotes neurite extension and provides neural protection in Alzheimer disease. TTR plays an important role in nerve regeneration process supporting a pivotal role for TTR in neurobiology. It regulates learning and memory process in the hippocampus and decreased expression of TTR leads to memory deficits in brain. It has been widely studied related to AD but further investigations are needed to explore its role in different brain-related diseases.
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