http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00417/full?
Xénia Latypova- Université de Nantes, Nantes, France
Around 44 million people in the world are suffering from
dementia including Alzheimer's disease (AD). It is considered as one of
the biggest global public health challenges our generation cope with.
At the dawn of 2015, AD medical care remains unsuccessful despite the
identification of its neuropathological hallmarks one century ago. Being
attentive to emerging prospects is essential because the current
advances lead to substantive improvement of the medical care. We are
pleased to present an issue specifically devoted to AD and to the
related therapeutic strategies. The Topic Research in this issue is
based on a series of original papers and reviews. The latters focus on
the advances in basic and clinical research trends in AD, they provide
an up-to-date information and future perspectives on this hot topic as
well.
AD is a progressive disease, it occurs over a long
period before the onset of symptoms which are impaired memory, apathy,
and depression. The characteristics of AD consist in neurofibrillary
tangles (intraneuronal aggregates of hyperphosphorylated tau proteins)
and senile plaques [dense extraneuronal deposits composed of amyloid β
(Aβ)]. The other features linked to these two core pathological
hallmarks of AD are inflammation, oxidative stress, progressive
synaptic, and neuronal loss. Nowadays, many AD molecular patterns have
been screened to identify a potential therapeutic strategy. Although a
myriad of evidence shows that the hippocampal volume decrease belongs to
the AD earliest signs, as it is pointed out by the authors of the
review paper presented in this issue, this element clearly could not be
used as a diagnostic criterion (Maruszak and Thuret, 2014).
With the flood of evidence for tau pathology as key
event of the disease development, the understanding of diverse tau
functions and its molecular behavior is one of the major steps in the
progression of our knowledge about the neurodegenerescence detected in
AD. The precision of tau role in DNA protection and RNA integrity under
physiological conditions or under ROS-producing stress (Violet et al., 2014)
provides clarification for a mechanistic model in which tau disturbance
initiates an explanation for DNA damages observed in AD. Principally,
tau is a phosphoprotein. So, a complex equilibrium between tau kinases
and phosphatases activities is one of the main potential therapeutic
runways. Abnormal or excessive tau phosphorylation by either kinases
such as GSK3β, CDK5, DYRK1A for example or other known and unknown
kinases are related to AD pathogenesis. However, the identity and the
strict number of tau kinases involved in AD process remain uncertain. In
this way, focus at specific tau phosphorylation site(s) by a kinase
multitargeting approach as potential AD therapeutic strategy has been
proposed to effectively hamper the multifactorial disease progression (Hilgeroth and Tell, 2013).
Since diabetes, linked itself to dysregulation of GSK3β activity, is
associated in late-life with an increased risk of dementia,
epidemiological and experimental studies are summarized in this issue in
order to understand the effects of diabetes mellitus on tau
pathogenesis. In fact, the authors discuss herein a link between tau,
diabetes mellitus and the cognitive impairment (El Khoury et al., 2014).
On the other hand, Peptidyl-prolyl cis-trans Isomerase NIMA-interacting
1 (Pin1), which plays a role in the balance of
phosphorylation/dephosphorylation of tau, has been suspected of
participating in a common mechanism between AD and hypoxia. The
pathophysiological relevance of Hypoxia-inducible factor 1α (HIF-1α)
pathway regulation in APP amyloidogenic metabolism has been explored in
order to clarify the relationship between AD and hypoxia (Lonati et al., 2014).
Among tau-based therapeutic strategies, the one which limits the
spreading of tau pathology without affecting tau intracellular functions
is especially attractive (Medina and Avila, 2014).
Strong support for this idea comes from the importance of tau for
Aβ-induced synaptotoxicity. In addition to this, high concentration of
Aβ inhibits synaptic activity and in turn, it involves toxicity for the
targeted synapses (Wang et al., 2013). According to this strategy, synaptic inhibitory systems could help to compensate neurotransmission imbalance (Nava-Mesa et al., 2014).
Moreover, natural anti-inflammatory components, as Andrean Compound,
has been studied as a preventive or adjuvant agent in AD (Maccioni et al., 2014).
Accumulation of Aβ is induced when the equilibrium
between its production and clearance is disrupted. Thus, amyloid-based
therapeutic strategies target this balance but numerous trials were
unsuccessful for reasons of specificity or biodisponibility. However,
the restoration of the microglial homeostasy and the targeting of
Triggering Receptor Expressed on Myeloid cells 2 (TREM2) pathway can
constitute an elegant therapeutic strategy (Zhao and Lukiw, 2013). Compounds are yet available to improve the microglia-dependent clearance of Aβ, and this strategy would benefit from in vivo experiments (Jones et al., 2014).
Furthermore, diversity of gut microbiota changes through life stages
and alterations of this ecosystem have been associated with diverse
diseases. Therapeutic modulation of gut microbiota could constitute a
promising adjuvant therapy in central neurodegenerative disorders. An
opinion article proposes probiotics as a prophylactic treatment to
prevent AD in its early stages (Bhattacharjee and Lukiw, 2013).
Several recent key advances in the field of AD
understanding and treatment are presented in this thematic issue.
Ultimately, we hope that you will enjoy as us to read these papers and
reviews presented in this special issue. The coming years certainly
promise a time for completion of a new era in the history of the AD
understanding and emerging therapies. AD understanding is within reach.
Stay tuned.
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