No abstract

We have disrupted the retinoid signalling pathway in adult rats by a dietary deficiency of vitamin A. After 1 year of this dietary deficiency, there was a deposition of amyloid beta in the cerebral blood vessels. There is a downregulation of retinoic acid receptor alpha in the forebrain neurons of the retinoid-deficient rats and a loss of choline acetyl transferase expression, which precedes amyloid beta deposition. In neocortex of pathology samples of patients with Alzheimer's disease, the same retinoic acid receptor alpha deficit in the surviving neurons was observed. We have identified the retinoid-synthesizing enzymes involved in this process, retinaldehyde dehydrogenase-2 and class IV alcohol dehydrogenase, only the former is downregulated in patients with Alzheimer's disease. This suggests that retinoids are important for the maintenance of the adult nervous system and their loss may in part play a role in Alzheimer's disease.

No abstract

The embryonic CNS readily undergoes regeneration, unlike the adult CNS, which has limited axonal repair after injury. Here we tested the hypothesis that retinoic acid receptor beta2 (RARbeta2), critical in development for neuronal growth, may enable adult neurons to grow in an inhibitory environment. Overexpression of RARbeta2 in adult rat dorsal root ganglion cultures increased intracellular levels of cyclic AMP and stimulated neurite outgrowth. Stable RARbeta2 expression in DRG neurons in vitro and in vivo enabled their axons to regenerate across the inhibitory dorsal root entry zone and project into the gray matter of the spinal cord. The regenerated neurons enhanced second-order neuronal activity in the spinal cord, and RARbeta2-treated rats showed highly significant improvement in sensorimotor tasks. These findings show that RARbeta2 induces axonal regeneration programs within injured neurons and may thus offer new therapeutic opportunities for CNS regeneration.

Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs

Retinoic acid, acting through the nuclear retinoic acid receptor β2(RARβ2), stimulates neurite outgrowth from peripheral nervous system tissue that has the capacity to regenerate neurites, namely, embryonic and adult dorsal root ganglia. Similarly, in central nervous system tissue that can regenerate, namely, embryonic mouse spinal cord, retinoic acid also stimulates neurite outgrowth and RARβ2 is upregulated. By contrast, in the adult mouse spinal cord, which cannot regenerate, no such upregulation of RARβ2 by retinoic acid is observed and no neurites are extended in vitro. To test our hypothesis that the upregulation of RARβ2 is crucial to neurite regeneration, we have transduced adult mouse or rat spinal cord in vitro with a minimal equine infectious anaemia virus vector expressing RARβ2. After transduction, prolific neurite outgrowth occurs. Outgrowth does not occur when the cord is transduced with a different isoform of RARβ nor does it occur following treatment with nerve growth factor. These data demonstrate that RARβ2 is involved in neurite outgrowth, at least in vitro, and that this gene may in the future be of some therapeutic use.

The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition in the brain, neuronal cell loss and cognitive decline. We show here that retinoic acid receptor (RAR)α signalling in vitro can prevent both intracellular and extracellular Aβ accumulation. RARα signalling increases the expression of a disintegrin and metalloprotease 10, an α-secretase that processes the amyloid precursor protein into the non-amyloidic pathway, thus reducing Aβ production. We also show that RARα agonists are neuroprotective, as they prevent Aβ-induced neuronal cell death in cortical cultures. If RARα agonists are given to the Tg2576 mouse, the normal Aβ production in their brains is suppressed. In contrast, neither RARβ nor γ-agonists affect Aβ production or Aβ-mediated neuronal cell death. Therefore, RARα agonists have therapeutic potential for the treatment of AD.