Alzheimer’s disease (AD) is the most common neurodegenerative diseases and represents more than 80% cases of dementia. It affects between 20 and 30 million people in the world and this number is expected to increase fourfold by 2050 with the aging of the population. It initially manifested by irritability, personality disorder, mental confusion and difficulty to perform daily tasks.

At the cellular level, the neuronal damage leads to cortical atrophy and then to patient death. AD is characterized by the extracellular presence in the brain of amyloid plaques formed mainly of β-amyloid peptide in the form of 42 amino acids (Aβ1-42) and intra-neuronal neurofibrillary tangles. Although no effective treatment exists to date, real efforts are in place to better understand the molecular origins of the disease, improve diagnosis and propose new therapeutic strategies.

Origin and pathophysiology of the disease

Alzheimer’s disease occurs sporadically in the majority of cases. Genetic forms nevertheless were identified essentially because of mutations in the gene encoding the precursor of the β-amyloid (Amyloid Precursor Protein or APP) or in the gene encoding for presenilin, a γ-secretase involved in the cleavage of the APP into Aß peptide. In all cases, it is observed an abnormal level of Aβ1-42 peptides that aggregate in oligomers and then that form later senile plaques. Recent studies have detected a spread “prion-like” of Aβ1-42 peptide between neurons and glial cells making difficult the containment of the disease.

Excessive accumulation of Aß oligomers occurs first in neurons and then spread in the surrounding neuropil. This leads to activation of nicotinic acetylcholine receptors present on astrocytes that cause the release of glutamate they have stored. This excess of glutamate causes an exacerbated activation of NMDA receptors localized on neurons leading to a strong increase of calcium influx, alteration of mitochondrial function, oxidative stress, hyperphosphorylation of Tau protein and, therefore, loss of synapses. Senile plaques for their part lead to activation of glial cells and involved inflammatory mechanisms as well as oligodendrocyte destruction.

The Home and School Reference Work, Volume I. Source: Sue Clark

The Home and School Reference Work, Volume I. Source: Sue Clark

Usual treatments

Today, there is still no cure. The only drugs approved by the FDA (U.S. Food and Drug Administration) are intended to reduce symptoms and slow the progression of the disease. Moreover, they can cause several secondary effects and some molecules eventually had to be taken off the market as Tacrine (COGNEX) an acetylcholinesterase inhibitor. Treatments are divided into two groups:

  • The acetylcholinesterase inhibitors help to stabilize the levels of acetylcholine in the brain and are intended to slow the memory loss:
  • The NMDA receptor antagonists (Memantine or EBIXA commercialized by Lundbeck) counteract the abnormally high levels of glutamate to reduce behavioral disorders; glutamatergic neurons being heavily involved in cognition, learning and memory.

New therapeutic targets

A better understanding of the molecular mechanisms underlying neurodegenerative events offer new therapeutic approaches that investigate different aspects of the disease:

  • Modulation of GABA (γ-aminobutyric acid) and Serotonin neurotransmitter levels

In the same way that the two classes of drugs already available, the modulation of the levels of other neurotransmitters is an attractive therapeutic target. Are targeted GABAergic and serotonergic transmission for their involvement in cognitive function, learning and memory. The SGS742 (develop for AD application by Saegis Pharmaceuticals), an antagonist of GABA B receptor and several agonists or antagonists of various serotonergic receptors are currently being tested in phase II trials after very encouraging preclinical results.

GABA and Serotonin

GABA and Serotonin

  • Restoration of mitochondrial function and reduction of oxidative stress

The accumulation of Aß alters mitochondrial function causing release of reactive oxygen species (ROS), and thus oxidative stress. Several drugs are being evaluated for their ability to prevent this impairment as Idebenone (Takeda Pharmaceuticals), an analogue of ubiquininone which acts as an electron carrier in the respiratory chain.

The combination of antioxidants (vitamin E, C, selenium, flavonoids and carotenoids) is also the subject of many studies since they have shown neuroprotective effects in several experimental models. Currently the combination of lipoic acid and omega-3 is in phase I/II trials (Oregon Health and Science University). Co-administration of vitamin E and memantine (Veterans Affairs Cooperative Studies Program) is in the phase III trials.

  • Modulation of Aβ signaling pathways

One of the therapeutic strategies aims to restore the imbalance between toxic and non-toxic forms of Aß. Indeed, it is the combined action of β-secretase and γ- secretase which lead to Aβ1-42 peptide but there are other forms of secretases (α-secretase) that cleave APP to give non-toxic forms. It is possible to modulate these signaling pathways, for example Bryostatin which activates the signaling cascade triggered by the α-secretase is currently in phase II trials (carried out by Blanchette Rockefeller Neurosciences Institute, BRNI). It is also possible to act on the intracellular signaling cascade of Aß. The phosphodiesterase (PDE) inhibitors that control the hydrolysis of cAMP and cGMP second messengers are key molecules since they are heavily involved in memory loss. Rolipram, an inhibitor of the PDE-4 is the first molecule able to effectively restore cognitive deficits in a mouse model of AD. An inhibitor of the PDE-5, Sildenafil produced similar results. Some of these inhibitors have recently entered clinical phase.

  • Blocking Tau hyperphosphorylation and stabilize microtubules

Under physiological conditions, the Tau protein stabilizes microtubules in axons and is essential for the proper neuronal functioning. Its hyperphosphorylation causes cellular alterations including failure of axonal transport. The inhibition of the enzymes involved in this mechanism as GSK-3 (Glycogen Synthase Kinase 3) is currently undergoing phase IIb trials (carried out by Meditex Pharma). Stabilization of microtubules by compounds like Paclitaxel also show beneficial effects on axonal transport and motor function in a mouse model of AD.

Crystallographic structure of human GSK-3.Source: BY-SA 3.0

Crystallographic structure of human GSK-3. Source: BY-SA 3.0

  • Preventing Aβ1-42 and Tau oligomer formation

Several molecules are designed to prevent oligomerization and aggregation of β-amyloid. For example, the compound ELND005 (Transition Therapeutics) is able to reduce cognitive deficits in mice and is currently in phase II trial. Other compounds have an anti-oligomerizing action both on the Aß peptide and on Tau protein as Methylthioninium chloride which improves axonal transport, decreases oxidative stress and prevents mitochondrial alterations in a murine model of AD.

  • Favoring Aβ1-42 and Tau oligomer degradation

Natural cellular mechanisms operate to remove the excess of β-amyloid as its proteolytic degradation, its capture by glial cells or its sequestration at the vascular level by LRP1 protein (Low Density Lipoprotein Receptor Related Protein 1). A therapeutic strategy aims to increase the cellular degradation faculties, cellular confinement or to block the binding of Aβ1-42 to several neuronal receptors for which Aß has a strong affinity. Among these molecules, the hormone Somatostatin increases clearance of oligomers Aß by activation of neprilysin, a metalloprotease. A similar approach is to increase the degradation of Tau protein. In this context, the curcurmin inhibiting the Hsp90 protein (Heat shock protein) known to block the degradation of Tau, is the subject of numerous studies in experimental models.

  • Therapeutic vaccination

Therapeutic vaccination with Aß oligomers is a new therapeutic strategy to generate anti-Aß antibodies and thus promote the natural degradation of the oligomer. Clinical trials begun in 2001 with AN1792 (Janssen), an synthetic Aβ1-42 peptide showed the presence of anti-Aß antibodies, decreased Tau levels in cerebrospinal fluid and a slowing of cognitive decline in patients. However, the tests were discontinued after the occurring of meningoencephalitis in 6% of patients. Therapeutic vaccination to promote the degradation of the hyperphosphorylated Tau oligomers is also considered.

  • Neuroprotection and Neurogenesis

Administration of hormones (estrogen, progesterone and testosterone) showed neuroprotective effects including improvement of neuronal viability and decrease of Aß and tau accumulation. Neurotrophic factors may also be used to stimulate neurogenesis and cell survival. The Cerebrolysin, peptide possessing neurotrophic properties improves the symptoms and slows the progression of the disease. It is currently being tested in combination with acetylcholinesterase inhibitors.

Source: Hey Paul Studios

Source: Hey Paul Studios

Thus, despite the complexity of AD, several promising new therapeutic strategies are developed and represent a real boom in the fight against the disease. These approaches not only aim to reduce symptoms but also to cure. It is the combination of drugs targeting different aspects of the pathology that could be the most promising.

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