Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer’s Disease and Frontotemporal Dementia

MAPT

The first evidence of a genetic cause for familial FTD came from the demonstration of a linkage with chromosome 17q21.2 in autosomal dominantly inherited form of FTD with parkinsonism [36], named FTDP-17. The gene responsible for such association, MAPT, was discovered few years later [37]. MAPT encodes the protein tau, which is involved in microtubule stabilization, assembly, and cytoskeletal dynamics [38]. It is composed of 15 exons and transcribed, by alternative splicing, in 6 different isoforms, all of which play a role in the maintenance of microtubular structure. Any excess of tau protein can be bundled into protein aggregates that fill the cells and induce neurotoxicity. Tau has four repeat domains in the C-terminus, which mediate the interaction with microtubules. These domains are encoded by exons 9–12, in which the majority of pathogenic mutations have been found. In addition, alternative splicing of exon 10 leads to two different isoforms that contain either three (3R) or four (4R) 31-amino acids repeats [39].

The pathology of all MAPT mutations is characterized by the deposition of insoluble aggregated tau proteins within neurons and glial cells in the cerebral cortex and in other brain regions.

To date, more than 40 pathogenic MAPT mutations have been described and classified according to their position in the gene [40], their effects on MAPT transcription, and the type of tauopathy. The frequency of MAPT mutations is highly variable, but in general MAPT mutations are very rare in sporadic patients, whereas in most familial cases the frequency ranges between 5% and 20% depending on the geographic distribution [41].

The pathogenic mechanism of each different mutation depends on the type and location of the genetic defect, and affects the normal function of tau, i.e., the stabilization of microtubules promoting their assembly by binding tubulin. Some mutations increase the free cytoplasmic portion of the protein promoting tau aggregation, while others lead to an aberrant phosphorylation of tau protein, which damages microtubule stabilization [41]. Regarding mutations localized in the donor splicing site following exon 10, it was shown that these intronic mutations increase the inclusion of MAPT exon 10 by destabilizing the stem-loop structure that spans the splice site of exon 10, resulting in an increased production of 4R tau. Mutations in the acceptor splicing site following exon 10 lead to an enhanced inclusion of this exon [42].

Alternatively, other mutations affect the alternative splicing, thus producing altered ratios of the different isoforms (3R/4R tau). Most of missense mutations, such as the p.P301L mutation, reduce the ability of tau to bind microtubules leading to a decreased tau capacity to promote microtubules assembly [43]. Moreover, it was observed in in vitro studies that several coding mutations accelerate the aggregation of tau [44]. In 2009, Rovelet-Lecrux and coworkers identified a heterozygous 17.3 Kb deletion responsible for the removal of exons 6–9 of MAPT in one FTD patient [45]. This deletion caused the loss of the first microtubule binding domain and a decrease in the binding abilities of tau to the microtubules. The same group reported a 439 Kb duplication in the region encompassing CRHR1, MAPT, and saithoin (STH) in one patient affected by behavioral and amnestic disorders [46].

The clinical presentation in MAPT mutation carriers is heterogeneous, but behavioral changes, semantic impairment, episodic memory decline, and parkinsonism have been proposed as key clinical features. From the pathological point of view, patients present atrophy of the frontotemporal lobes and basal ganglia and variable presences of tau-positive inclusions, typical of FTLD-tau [47].

GRN

After the discovery of MAPT as causal gene for FTDP-17, there were still numerous autosomal dominant FTD cases genetically linked to the same chromosomal region of MAPT (chr17q21), without any mutation in MAPT, in spite of an extensive fine mapping of the gene. A small region rich in genes, localized approximately 6.2 Mb in physical distance to MAPT locus, had been recognized as that one containing the gene responsible for the disease in these families. The first identified mutation in GRN, identified in 2006, consisted of a 4-bp insertion of CTGC between coding nucleotides 90 and 91, causing a frameshift and premature termination in progranulin (C31LfsX34) [48]. In a parallel study, Cruts and co-workers found at the same time another mutation of five base pairs into the intron following the first non-coding exon of GRN (IVS1+5G>C) [49]. This mutation causes the splicing out of the intron 0, leading the retention of mRNA within the nucleus and its degradation.

GRN mutations were subsequently found to account for 5–20% of FTD patients with positive family history and 1–5% of apparently sporadic patients [50].

GRN encodes for the growth regulation factor named progranulin. Progranulin is an 88 kDa secreted glycoprotein, which in brain is expressed by neurons and microglia [51]. Its expression is low in early development and increases with age. The protein is composed by seven and one half cysteine-rich granulin domains and can be cleaved by several proteases into 6 KDa units called granulins. It belongs to a family of proteins involved in multiple biological functions, including development, wound repair, and inflammation, by activating signaling cascades that control cell cycle progression and cell motility [51].

Since the original identification of null-mutations in FTLD, more than 70 different mutations have been described so far. Most of the known pathogenic GRN mutations, particularly frameshift, splice-site, and nonsense mutations, are predicted to result in a premature stop codon. The resulting aberrant mRNA is degraded through the process of nonsense mediated decay, leading to haploinsufficiency [52]. Also rare partial deletions and a complete deletion of the gene have been described [53].

At neuropathological examination, GRN-mutated FTD cases displayed ubiquitin-positive, tau-negative inclusions (FTLD-U) similar to the microvacuolar-type still observed in a large proportion of apparently sporadic FTD, that were different from the tau-positive inclusions typical of MAPT mutated cases. Truncated and hyperphosphorylated isoforms of the TAR DNA binding Protein (TDP-43) were recognized as main components of the ubiquitin-positive inclusions typical of the GRN mutated families, as well as of idiopathic FTD and of a proportion of cases of amyotrophic lateral sclerosis (ALS) [54]. According to the novel neuropathological classification of FTLD-TDP pathology in FTD [55], TDP-43 neuropathological subtype A is consistently found in association with GRN-mutated cases.

A collaborative study [53] analyzing GRN mutations in 434 patients estimates a frequency of 6.9% of all included FTD-spectrum cases. About 56% of such cases was represented by FTD subjects with ubiquitinated inclusions at the neuropathology (FTD-U) with a positive family history of FTD.

From the clinical point of view, mutations in GRN are associated with extremely heterogeneous phenotypes, but the main clinical diagnosis is FTD following by diagnosis of primary progressive aphasia [56]. Language impairment seems to be more relevant as the disease progresses. About 40% of patients have parkinsonism, and episodic memory impairment is frequently observed, leading to a clinical diagnosis of AD in some cases [57]. Although rarely, an overlap between psychiatric disorders and genetically determined FTD can occur, as shown by Rainero et al. [58], who described a patient with heterosexual pedophilia who was a carrier of a GRN mutation and developed FTD over time, and by Cerami et al. [59], who reported two clinically different, apparently sporadic FTD cases sharing the Thr272fs GRN mutation, who had a premorbid bipolar disorder history.

The penetrance for GRN mutations is age dependent with only 50% of GRN mutation carriers affected at the age of 60 and 90% of mutation carriers affected at 70 years of age. Age at disease onset is extremely wide, even in the same family, ranging from 47 to 79 years [60]. In a large Calabrian family harboring a heterozygous c.1145insA mutation, the age at onset ranged from 35 to 87 years whereas the age of death was from 56 to 87 years [61]. In that family, the clinical presentation was homogenous; all of affected members had clinical diagnosis of FTD with subsequent language impairment.

A major contribution to achieve a correct diagnosis independent of the phenotypic presentation is the demonstration that progranulin plasma levels are extremely low in GRN mutation carriers, even in asymptomatic subjects [62, 63].

Regarding the function of progranulin, Pickford et al. [64] demonstrated, in an in vitro model, that it has chemotactic properties toward cultured mouse neurons. In addition, progranulin-treated primary neurons secrete a number of cytokines and chemokines, particularly those involved in proliferation (i.e., IL-4), and, importantly, induce microglia to switch from a pro-inflammatory to an anti-inflammatory phenotype [64]. Another recent observation is that progranulin binds the Tumor Necrosis Factor Receptor (TNFR)2, that is expressed specifically in neuronal subtypes and glial cells in the brain, leading to an anti-inflammatory cascade [65].

Abnormalities of several cytokines and chemokines has been observed in cerebrospinal fluid (CSF) of GRN carriers compared with controls [66], suggesting an imbalance of specific inflammatory factors possibly related to GRN haploinsufficiency.

C9ORF72

One of the most intriguing discoveries in the genetics of FTD has been the investigation of FTD/motor neuron disease (MND) families linked to a locus on chromosome 9q21-22. The first evidence of linkage with this locus comes from a study carried out in families with autosomal dominant FTD-MND [67]. Additional data confirmed the linkage to chr9q21-22 in FTD-MND families [68], until, in 2011, two international groups identified the gene responsible for the disease in this locus, C9ORF72. The mutation consists of a large hexanucleotide (GGGGCC) repeat expansion in the first intron of the gene.

In healthy subjects, most individuals carry between 2 and 20 repeats, but FTD and ALS patients had from 100 to also 1000 s of copies of repeats. The minimum repeat length to confer risk of disease is unknown, probably due to the presence of somatic mosaicism. In fact, the length of repeats is different between tissues even in the same individual and this phenomenon complicates genotype-phenotype correlation studies [71].

C9ORF72 repeat expansion is the most common cause of FTD (with or without ALS) worldwide. There is a particular high frequency in a Finland population, probably due to a common founder. Studies in Asian cohorts have reported instead much lower frequencies [72].

Clinical phenotypes are very variable [73] as well as the age at onset and disease duration; in fact, age at onset can range between 27 and 83 years and disease duration from 1 to 22 years. The most common clinical presentation is FTD, ALS, or both. As mentioned above, in families where FTD-ALS is the clinical phenotype, the C9ORF72 repeat expansion is very common, explaining the disease in more than 50% of families [74]. FTD patients present behavioral disturbances, whereas language impairment is less commonly observed [75]. In addition to classical behavioral presentations, such as apathy, disinhibition, socially inappropriate conduct, and loss of empathy, C9ORF72 expansion carriers present a high frequency of hallucinations, psychosis, and delusions [76], which lead to a primary diagnosis of schizophrenia and bipolar disorders [77, 78]. Sometimes patients have episodic memory problems at the beginning of the disease course, receiving a primary diagnosis of AD [76, 79]. Less than 1% of clinically diagnosed AD patients carry a C9ORF72 expansion with TDP43 pathology [79]. Other studies [80] found no C9ORF72 expansions in AD patients, suggesting the total frequency of C9ORF72 positive cases in AD is very rare (<1%). Most likely, there is no association between AD and C9ORF72. Likely, some AD cases have been misdiagnosed or some expansions are not big enough to be causal. Early-parkinsonism has also been reported in C9ORF72 expansion carriers, although very rarely in MAPT and GRN mutation carriers [76].

From a neuropathological point of view, postmortem examination showed that C9ORF72 expansion carriers present TDP-43 positive inclusions in different brain areas. Most patients present with FTLD-TDP type A or B [55]. In addition, they have neuronal inclusions in the cerebellar granule cell layer, hippocampal pyramidal neurons, and other anatomic sites that are positive for ubiquitin and p62 proteins. These inclusions are composed by dipeptide repeat proteins (DPRs), translated from the GGGGCC repeat through unconventional repeat-associated non-ATG translation. Poly-GP, Poly-GA, and Poly-GR are generated from sense strand and detected in hippocampus and cerebellum of expansion carriers [81]. Normal C9ORF72 functions were reported to be involved in the nucleocytoplasmic transport, autophagy, intercellular trafficking, and TDP-43 aggregation (see [82] for review).

Reddy et al. [83] demonstrated that the r(GGGGCC)n RNA forms extremely stable G-quadruplex structures, which theoretically may affect promoter activity, genetic instability, RNA splicing, translation and neurite mRNA localization.

Moreover, several studies, conducted in derived cells and tissue of patients, demonstrated that these foci are able to sequester RNA binding protein, including hnRNP h, hnRNP A1, and SC35, affecting the mRNA nuclear transport system [84]. However, the clear mechanism linking RNA foci and sequestered proteins to neurodegeneration has not been fully understood. Together with the formation of RNA foci and DPR, another suggested pathological mechanism of the C9ORF72 expansion is gene downregulation due to C9ORF72 methylation [85].

In cultured cells and primary neurons, Poly-GA overexpression led to the generation of p62-positive inclusions and neurotoxicity attributed to impaired ubiquitin proteasome function [86]. On the other hand, arginine-rich dipeptide (poly-GR and poly-PR) led to the formation of nucleolar inclusions in fly models [87]. Since the clinical utility as well as the significance and the temporal course of DPRs in the pathogenesis of the disease is still unclear, Lehmer et al. [88] established a poly-GP immunoassay from CSF in order to identify and characterize C9ORF72 patients. Intriguingly, they observed Poly-GP CSF levels were already detectable in C9ORF72 asymptomatic carriers compared to healthy subjects and these levels are similar in symptomatic expansion carriers, demonstrating a possible use as a diagnostic biomarker in addition to genetic screening [88].

CHMP2B

Few FTLD families display mutations in the charged multivesicular body protein 2B gene (CHMP2B), which encodes a component of the heteromeric ESCRT III complex, involved in the endosomal trafficking and degradation [89]. CHMP2B is involved in sorting and trafficking surface receptors or proteins into intraluminal vesicles for lysosomal degradation and binding the Vps4 protein responsible for the dissociation of ESCRT components [90]. The first mutation in CHMP2B was identified in one large kindred from Denmark [91]. Behavioral and cognitive impairment associated with extrapyramidal and pyramidal signs are the main clinical manifestations in CHMP2B.

All mutations described (missense and truncation mutations) show a common mechanism of action: the deletion of the C-terminus of the protein with the loss of the Vsp-4 binding domain [90]. This causes the accumulation of mutated CHMP2B on the endosomal membrane and prevent the recruitment of other proteins necessary for endosomal fusion with lysosomal. This phenomenon leads to the impairment of the late endosomal trafficking and contributes to neurodegenerative processes in FTD [91]. This can be observed as enlarged and abnormal endosomal structures in postmortem brain tissue from patients [92]. From a histological point of view, patients with CHMP2B mutations present FTLD-U with ubiquitin- and p62-positive but TDP-43-negative neuronal cytoplasmic inclusions [93].

VCP-1 and SQSTM1

Mutations in the Valosin Containg Protein gene (VCP) were firstly described as cause of hereditary inclusion body myopathy with Paget’s disease of the bone (PDB) and FTD [94]. Myopathy is the most frequent clinical symptom, present in about 90% of affected subjects, whereas FTD is seen in about 33%, usually many years after the onset of muscle symptoms. From a histological point of view, brain tissues of patients carrying VCP mutations are characterized by FTLD-TDP type D pathology with TDP43 and p62 positive inclusions within neuronal nuclei [95].

VCP-1 encodes a monomeric protein composed of 806 aminoacids. It is known as a regulator of many cellular processes, such as ubiquitin-dependent protein quality control, labeling proteins for degradation, and coordination of the removal of protein aggregates via multivesicular body formation [96].

Another gene involved in the mechanism of protein degradation as well as in FTLD pathogenesis is Sequestosome 1 gene (SQSTM1). This gene encodes for p62 protein, a connector between ubiquitinated proteins and autophagy receptor or proteasome degradation pathways [97]. Mutations in SQSTM1 were first described in PDB and are responsible for around 30% of familial PDB cases (see [98] for review). In 2014, Van der Zee et al. published a large-scale resequencing study in an FTLD cohort of patients and identified a number of mutations in the C-terminal of the gene that is involved in the binding with ubiquitinated proteins [99].

CHCHD10

A coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) gene encodes a mitochondrial protein that is enriched at cristae junctions in the intermembrane space. By exome sequencing, it was possible to identify the first pathogenic mutation, p.S59L, in an atypical family with late onset MND, FTD, cerebellar ataxia, and mitochondrial myopathy [100]. Subsequent genetic studies identified additional potential pathogenic mutation in FTD and ALS patients with 1–3% frequency [101]. Very recently, Perrone et al. identified a novel nonsense mutation (p.Gln108*) in a patient with atypical clinical FTD and pathology-confirmed Parkinson’s disease (1/459, 0.22%) leading to loss of transcript. They further observed three previously described missense variants (p.Pro34Ser, p.Pro80Leu, and p.Pro96Thr) that were also present in the matched control series [102].

TBK1

In 2015, a large exome sequencing case-control study identified mutations in the TANK binding kinase 1 gene (TBK1) in sporadic ALS cohort of patients [103]. Subsequent studied showed TBK1 loss of function mutations in families with FTD-ALS but also in clinical FTD and pathologically confirmed FTLD-TDP even in the absence of motor neuron disease [104]. The majority of mutations identified are loss-of-function mutations leading to a decrease 50% of TBK1 expression. Missense mutations instead impair the binding of TBK1 to optineurin (OPTN). As VCP or p62, TBK1 is also involved in protein degradation and autophagy mechanisms. In fact, it phosphorylates p62 and OPTN, another member of the autophagy pathway. In 2015, Potteir et al. discovered, in a pathologically confirmed cohort of patients, one heterozygous mutation and one deletion in OPTN as well as a nonsense mutation in TBK1 suggesting that both genes contribute to FTLD-TDP etiology [104].

TARDBP

TARDBP encodes for TDP-43 protein, which is localized in the nucleus of the cell, where it is able to form heterogeneous nuclear ribonucleoprotein (hnRNP) complexes with several functions, such as RNA regulation, mRNA stability and transport, and splicing control. A link between FTLD and ALS and TDP-43 was supported by the evidence that TDP-43 regulate axon growth in vivo and in vitro suggesting that the capacity of motor neuron to produce and maintain axons is compromised by TDP-43 dysregulation [105].

FUS

Similar to TDP-43, Fused in sarcoma (FUS) is highly conserved and ubiquitously expressed gene. FUS is a component of the hnRNP complex and involved in RNA transport in and out of the nucleus, RNA splicing, and DNA/RNA metabolism [106]. In 2009, FUS mutations were discovered to be the cause of 3% of familial ALS. They are mostly located in the C-terminal of the protein, particularly in the nuclear localization sequence, resulting in an impairment of transportin (TRN1)-mediated nuclear import of FUS [106]. Neuropathologically, ALS patients with FUS mutations display abnormal cytoplasmic neuronal and glial inclusions positive for FUS. However, in some FTLD-FUS patients, no FUS mutations have been identified.

UBQLN2

UBQLN2 is involved in a rare form of chromosome X-linked familial ALS and FTLD-ALS [107]. Mutations are located in proline residues in the highly conserved PXXP repeat domain involved in the degradation of misfolded proteins via ubiquitin proteasome system and autophagy.

TUBA4A

TUBA4A encodes 1 of 8 human a-tubulins, which polymerize with b-tubulins to form the microtubule cytoskeleton. TUBA4A mutations have primarily been associated with ALS, although some patients also had cognitive involvement ranging from mild cognitive impairment to FTD. In TUBA4A, 10 missense, 1 nonsense, and 1 splice donor site mutation have been identified in both sporadic and familial ALS patients, with some also presenting with FTD [102].

Methylation

DNA methylation is the best characterized epigenetic modification that involves the addition of a methyl group to the carbon-5 of a cytosine residue in DNA and is carried out by one of the several DNA methyltranferase (DNMT) enzymes. DNMT1 is the enzyme responsible for the maintenance of DNA methylation patterns during DNA replication. It localizes to the DNA replication fork, where it methylates nascent DNA strands at the same locations as in the template strand [117]. DNMT3a and DNMT3b are involved in the de novo methylation of unmethylated and hemimethylated sites in nuclear and mitochondrial DNA, respectively [117, 118]. In mammals, DNA methylation occurs predominantly at CpG sites-locations, where a cytosine nucleotide is followed by a guanine nucleotide. CpG sites can occur in concentrations of up to several hundred dinucleotide repeats, called CpG islands, which are frequently found in gene promoters. The methylation or hypermethylation of CpG islands usually prevents the expression of the downstream gene [119]. DNA methylation is currently the best understood epigenetic mechanisms, and is known to have a crucial role in normal development, cell proliferation, and genome stability [120]. In addition, non-CpG methylation may happen in stem cells and neurons [121].

Early epigenetic investigations related to AD focused on DNA methylation, finding non AD specific hypomethylation of the APP gene promoter region in one patient [122].

More recent studies support an overall reduction in DNA methylation in AD patients thus highlighting the importance of DNA methylation in AD [123]. Interestingly Aβ has also been implicated as a trigger of epigenetic changes as it was found that Aβ induces global DNA hypomethylation [124]. Moreover, a DNA methylome paper found genes with altered methylation in AD brains [125].

Tau gene expression is also subject to complex epigenetic regulation, involving differentially methylated binding sites for transcription factors [126].

Recently, Bollati and colleagues investigated the methylation status of repetitive elements in blood, including Arthrobacter luteus elements (Alu) blood, long interspersed element 1 (LINE-1), and satellite-α (SAT-α), that comprise a wide portion of the human genome and are known to contain large numbers of CpG sites. They found that LINE-1 methylation was increased in AD patients and that enhanced LINE-1 methylation was associated with a better cognitive performance in AD patients [127].

Regarding FTD, two studies analyzed the GRN promoter methylation in relation to its ability to regulate progranulin expression. They found that increased methylation in FTD subjects negatively correlates with GRN mRNA levels [128, 129].

A recent GWAS on DNA methylation pattern in peripheral blood of patients with FTD and progressive supranuclear palsy compared to healthy subjects found a specific methylation signature associated pathologically with tauopathy, suggesting this signature as a risk factor for neurodegeneration [130].

Regarding the C9ORF72 expansion, it was suggested that the length of the repeat might influence the level of DNA methylation at the C9ORF72 promoter. This process was found in a family from Canada with the father carrying an intermediate length allele, about 70 repeats, with an unmethylated C9ORF72 promoter, that expanded to about 1750 repeats in his children. The expanded allele carried by the four children was characterized by C9ORF72 promoter hypermethylation and associated with reduced C9ORF72 expression [131]. Recent findings demonstrated that DNA hypermethylation was found in the 5’ CpG region (∼36% ALS cases), as well as the C9ORF72 repeat itself in both ALS and FTD patients (∼100%) [132, 133].

ncRNAs

It was widely believed in the past that most of the human genome consisted in “non-functional” DNA. It was later discovered that almost the whole genome is transcribed, but that just about 2% in translated into proteins [134].

It is now instead ascertained that most of this “junk” is functional and composed by ncRNA, whose signaling and editing is able to play a crucial role in chromatin and nuclear structure. In particular, ncRNAs are involved in epigenetic regulation by recruiting chromatin-modifying complexes. ncRNAs operate through repressive control but have also the potential to act as gene activators [134].

ncRNAs comprise small RNAs (sRNAs) of less than 200 nucleotides and long non coding RNA (lncRNAs) of more than 200 nucleotides. sRNAs are further subdivided as micro (mi)RNAs, short interfering (si)RNAs, and PIWI-associated (pi)RNAs, whereas lncRNA are categorized according to their direction and position of their transcription in: antisense, intergenic, exonic, intronic, overlapping [135].

miRNAs are single stranded, non-coding small RNAs that are abundant in plants and animals, and are conserved across species [136]. The raw transcripts undergo several nuclear and cytoplasmic post-translation processing steps to generate mature, functional miRNAs. In the cytoplasm, mature miRNAs associate with other proteins to form the RNA-Induced Silencing Complex (RISC), enabling the miRNA to imperfectly pair with cognate miRNA transcripts. The target mRNA is then degraded by the RISC, preventing its translation into protein [137, 138]. miRNA-mediated repression of translation is involved in many cellular processes, such as differentiation, proliferation, and apoptosis, as well as other key cellular mechanisms [139, 140].

It is now well established that altered RNA processing could act as a contributing factor to several neurological conditions including aging-related neurodegenerative diseases such as AD, FTD, ALS, and Parkinson’s disease [141–143].

In AD, the implication of miRNAs in Aβ production, via BACE1 modulation, and in tau phosphorylation, that leads to hyperphosphorylated neurofibrillary tangle formation, has been demonstrated [142].

Altered miRNA signatures were also identified in AD and FTD. In particular, several miRNAs have identified differentially expressed in postmortem tissue, blood, and CSF that also differ by disease stage [145, 146].

Regarding lncRNAs, they also have been involved in neurodegenerative diseases [146].

These ncRNAs are involved in different functions; they act as scaffolds for chromatin modifiers and nuclear paraspeckles, as transcriptional co-regulators, and even as decoys for other RNAs [145]. Dysregulations in lncRNAs can influence any one of these processes, thus contributing to neurodegeneration. lncRNAs associated with disease condition can post-transcriptionally increase gene expression, as it happens with the lncRNA BACE1-antisense whose expression is selectively increased in AD brains and competes with miR-545-5p binding to stabilize BACE1 mRNA. This will finally result in increased expression of BACE1 that contribute to the formation of the toxic Aβ peptides that is a major hallmark for AD [146].

Another lncRNA, BC200, likely plays a role in AD as increased levels were found in specific brain regions mostly affected by AD, such as the Brodmann’s area 9 [147]. MALAT1 and NEAT1 are other two lncRNAs very important for splicing and synapse formation [148, 149].

Chromatin remodeling

In mammalian cells, histone proteins interact with DNA to form chromatin, the packaged form of DNA. Histones are octamer consisting of two copies of each of the four histone proteins: H2A, H2B, H3, and H4. Each histone octamer constitutes in 146 bp of the DNA stand wound around it to make up one nucleosome, which is the basic unit of chromatin. Histone proteins can be modified by post translational changes, including: acetylation, methylation, phosphorylation, ubiquitination, and citrullination. These histone modifications induce changes to the structure of chromatin and thereby affect the accessibility of the DNA strand to transcriptional enzymes, resulting in activation or repression of genes associated with the modified histone [150]. The best-understood histone modification is acetylation, which is mediated by histone acetyltransferases and deacetylases [151]. Acetylation of histones is usually associated with upregulated transcriptional activity of the associated gene, whereas deacetylation of histones to transcriptional silencing [152].

Histone acetylation was found to be largely decreased in the temporal lobe of AD patients compared to controls and in mouse models of AD [153]. Moreover, increased H3 acetylation at the promoter region of the BACE1 gene in AD patients was found [153].

Besides acetylation, different forms of histone methylation exist [154], and may be linked to neurodegenerative diseases.