Brain aging, epigenetic changes, tau and neurodegeneration

1. Introduction

In this short review, I comment about the epigenetic modifications that occur during brain aging. Such alterations may have a variety of effects, including a decrease in the rate of adult neurogenesis in the dentate gyrus (DG). The induction or elimination of epigenetic alterations may be reversible. I propose that epigenetic changes can be erased by the expression of Yamanaka factors, thereby recovering brain functions. Furthermore, in the brain, age-dependent epigenetic modifications can be promoted by neuron-specific proteins like tau. Thus, an increase in neuronal tau would facilitate neurodegeneration.

2. Aging in peripheral tissues

Aging is the main risk for many serious health problems, including cancer, cardiovascular disease and neurodegenerative disorders like Alzheimer Disease (AD). During aging, cell DNA can be modified by somatic mutations, telomere shortening, and other features promoted by external factors that can also lead to the presence of epigenetic alterations [1], [2]. Overall, changes in the expression of the genome during aging result in “age-specific” RNAs or proteins and in changes (aging) at the cellular or tissue level. A scheme depicting cell differentiation and aging is provided in Fig. 1. In peripheral tissues, old cells are replaced by new ones. For example, in a young human being, skin cells are renewed about every month, while regeneration takes longer in old subjects. The new born cells derive from precursors (stem cells) that differentiate to form these new cells of the tissue in question.

Fig. 1.

Cell aging. The steps of the transition from embryonic to senescent cells involving epigenetic modifications are indicated. Recent studies [7] have indicated that epigenetic reprogramming (erasing) occurs in peripheral tissues. Little is known about neuronal tissues [31].

The lack of stem cells or the presence of damaged stem cells can increase the number of senescent cells, thereby promoting tissue degeneration. The expression of the genomes of these senescent cells is altered, which can lead to the secretion of toxic compounds, which in turn can damage neighboring cells. The presence of toxic factors can cause systemic chronic inflammation, which triggers several co-lateral disorders. The body reacts to chronic inflammation by prompting an immune reaction, which, in several organisms, is determined by the ratio of myeloid to lymphoid cells. Thus, it appears that in those organisms longevity may be immune-mediated [3].

In the Central Nervous System (CNS), myeloid cells like microglia [4] participate in this inflammation-like process [5].

3. Cell age

Cell age can be predicted by examining the “epigenetic clock” [6]. For example, biological age can be estimated by studying DNA methylation levels using machine-learning algorithms [6]. Also, other markers, based on epigenetic changes, like histone modifications, can be used for this purpose.

During aging, stem cells can also be modified by epigenetic alterations [7], [8] and they decrease the rate of renewal and become aged or can even die, thereby leading to the depletion of this cell population, thus impairing tissue replacement.

4. Brain, aging and Alzheimer’s disease

Brain aging is the main risk for AD. Two main pathological hallmarks have been reported in this disease, namely senile plaques (aggregates of amyloid peptide) and neurofibrillary tangles (composed by tau protein). Amyloid peptide and tau protein have been used as biomarkers to monitor AD pathology. However, there is no overlap between amyloid and tau pathologies [9] as the former precedes the latter [10]. An example of that is that amyloid aggregates cause the hyperactivation of neurons [11], and this in turn increases the translation of tau protein [12], thereby inducing accelerated cortical aging [10].

Another example is the reported novel connection between amyloid peptide and tau protein pathologies that has recently been put forward [13]. In this regard, it has been proposed that amyloid peptide activates microglia and that these cells facilitate the progression of tau pathology [14] and the activation of the NLRP3 inflammasome. Of note, the suppression of NLRP3 activity increases longevity [15].

Regarding the localization of pathology, an initial target for tau pathology is the entorhinal cortex and the hippocampal region, the latter involved in adult human neurogenesis [16]. Afterwards, tau pathology propagates, with amyloid aggregates playing a role in this spread [17].

5. Epigenetics and brain aging

As indicated, epigenetic modifications in the genome accumulate during brain aging [7]. During aging, neuronal DNA is altered by somatic mutations or by epigenetic modifications. In this review, I focus on the epigenetic modifications. These alterations can accumulate over time and promote changes in neuronal behavior. The accumulation and aggregation of proteins in neuronal cells may result in neuron degeneration and memory impairment, a feature of AD. Both, degenerated or non-functional newborn hippocampal neurons in the DG participate in the process that leads to the impairment of episodic memory [16]. Neuronal death results in the release of intracellular compounds into the extracellular space, where they become toxic. Intracellular tau protein is one such compound, becoming extracellular after neuron damage. The spread of extracellular tau can damage neighboring neurons [18], thereby propagating tau pathology throughout the brains of AD patients.

Research efforts are currently being devoted to the possible relation between tau pathology and epigenetic changes (see below).

6. Tau and epigenetic changes

A relationship between the presence of tau and epigenetic modifications has been described. Tau deficiency leads to the up-regulation of the protein B57 [19], which interacts with Co-REST, a protein involved in the repression of neuron-specific genes. Co-REST recruits REST complex and other proteins, and the resulting protein complex regulates epigenetic modifications (in histones), like deacetylation or methylation through the presence of histone deacetylases or methyltransferases [20]. Tau itself has even been described to exert intrinsic acetyltransferase activity [21]. In summary, tau participates in epigenetic modifications that contribute to accelerated aging. Given this consideration, strategies to decrease the amount of this protein in neurons emerge as potential therapeutic approaches, in tauopathies.

Also, tau may activate the expression of transposable elements in aging. Transposable elements are genetic sequences that can jump between sites in the genome. These changes in position can be prevented in young animals by epigenetic defenses, which are based mainly on the function of the Piwi-PiRNA pathway [22], [23]. However, an increase in tau expression impairs these epigenetic defenses, thus allowing transposon jumping, and accelerated aging [24], [25], which may result in neurodegeneration.

7. Adult hippocampal neurogenesis, aging and AD

Adult neurogenesis in the DG is decreased in AD patients [16]. This observation may facilitate the identification of a missing piece of the AD puzzle since preliminary experiments suggest that aging-induced epigenetic changes in neuronal (stem) cells are responsible for the impairment of adult hippocampal neurogenesis (AHN) in this disease [26]. Possible factors involved in accelerated aging related to AD may promote epigenetic changes in newborn adult neural stem cells [8], [27]. In this regard, the prevention [16] or rejuvenation of neuronal stem cells emerges as an interesting therapeutic option. One approach in this direction would be to erase the induced epigenetic changes. Indeed, epigenomic editing has been proposed as a strategy to tackle brain disorders [28].

8. Tau and adult neurogenesis

Tau deficiency has a slight effect on AHN in resting conditions [29]. However, under negative (Porsolt’s test) or positive (enrichment environment) conditions, newborn granule cells show decreased synaptic plasticity [29]. Furthermore, a transgenic mouse with an excess of phosphorylated tau shows aberrant AHN. Newborn neurons in this model show an aberrant morphology, similar to that found in DG neurons present in AD patients [30]. Thus, the presence of excess phosphosphorylated tau, but not the absence of this protein, impairs AHN.

AD has three specific features that are not present in other neurodegenerative disorders, namely a) pathological accelerated aging (the main risk factor for the disease), b) amyloid and tau pathologies, and c) memory impairment related to the lack of neuronal function in the hippocampal region (DG) and impaired AHN [16].

We have focused on the risk factors that can accelerate aging. These changes may occur through epigenetic modifications in neuronal precursors of adult hippocampal newborn neurons, which are involved in the onset of episodic memory.

In other words, it can be postulated that memory impairment is the result of deficient AHN. This deficiency arises from the accumulation of epigenetic changes in neuronal precursors during aging. Thus, the removal of these changes may facilitate the restoration of AHN. In this regard, it would be timely to test whether erasing epigenetic modifications in stem cells can reverse the consequences of accelerated aging.

9. Erasing epigenetic changes in the brain

Therefore, erasing such alterations emerges as a potential approach to rejuvenate old cells. Indeed, the reversal of age-associated hallmarks has been achieved in peripheral tissues by partial reprogramming [7] upon expression of the so-called Yamanaka factors (YFs) [7]. However, little is known about the effect of these factors on the CNS.

YF expression in aged neuronal cells might offer an approach to eliminate epigenetic marks. In this regard, preliminary results from my group indicate that in vivo reprogramming by YFs ameliorates the features of aging in DG cells and improves memory in aged mice [31]. That study revealed that the expression of YFs reduced the presence of aged DG neuronal cells, as determined by the level of H3K9me3, a well-known marker of aging. The expression of YFs mainly reprogrammed mature neurons, although some effect on AHN was also observed. In mature neurons, the presence of YFs increased the expression of the NMDA receptor subunit GluN2B, a molecule presents mainly in the brains of young animals. In addition, YF expression enhanced the memory index, as determined by the object recognition test [31]. Thus, YFs may clear epigenetic modifications, thereby “reprogramming” old DG neurons. Further work addressing the reprogramming of other regions of the brain would be of interest.

In summary, aging-related epigenetic changes can be induced by factors that accelerate aging or can be reversed by the expression of YFs. Some of these epigenetic alterations could be common to normal aging and AD. However, further studies will be needed to differentiate between these two conditions.

Biography

Jesús Avilais professor Autonomous University, Madrid, Spain. He is a Fellow of the Academia Europaea, the American Association for the Advancement of Science (AAAS) and the Spanish Royal Academy, and Member of the European Molecular Biology Organization (EMBO). He previously directed the Spanish National Research Council (CSIC) Center of Molecular Biology. His laboratory has made pioneering contributions to our knowledge of the neuronal cytoskeleton, in particular with respect to tauopathies such as Alzheimer’s disease.