Abstract
We have previously shown that the natural alkaloid anatabine displays some anti-inflammatory and Alzheimer amyloid (Aβ) lowering properties in the central nervous system associated with reduced STAT3 and NFkB activation. We investigated here the impact of a chronic oral treatment with anatabine in a model of tauopathy. We found that anatabine reduces the incidence of paralysis and abnormal hind limb extension reflex while improving rotarod performances in P301S mutant human Tau transgenic mice (Tg Tau P301S) suggesting that anatabine delays the disease progression in this model of tauopathy. Analyzes of brain and spinal cord homogenates reveal that anatabine reduces tau phosphorylation at multiple pertinent Alzheimer’s disease (AD) epitopes and decreases the levels of pathological tau conformers/oligomers in both detergent soluble and insoluble fractions. Pathological tau species reduction induced by anatabine was accompanied by decreased Iba1 expression suggesting a diminution of microgliosis in the brain and spinal cord of Tg Tau P301S mice. In addition, we found that anatabine administration increases phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3β, a primary tau kinase, associated with AD pathology, providing a possible mechanism for the observed reduction of tau phosphorylation. These data support further exploration of anatabine as a possible disease modifying agent for neurodegenerative tauopathies and, in particular AD, since anatabine also displays Aβ lowering properties.
Highlights
Alzheimer’s disease (AD), the most prevalent form of dementia in the elderly, is a progressive neurodegenerative disorder characterized by a loss of cognitive functions and by diverse psychiatric symptoms leading to confusion, agitation and aggression which constitute a major cause of patient distress
44 % (4 out of 9 non-paralyzed mice) of the placebo group (33 week-old mice) elicited an abnormal hind-limb extension reflex when suspended by the tail compared to 18% (2 out of 11) of Tg Tau P301S mice treated with anatabine (Figure 1)
Tg Tau P301S mice treated with anatabine showed an increased latency to fall (T-test, P
Summary
Alzheimer’s disease (AD), the most prevalent form of dementia in the elderly, is a progressive neurodegenerative disorder characterized by a loss of cognitive functions and by diverse psychiatric symptoms leading to confusion, agitation and aggression which constitute a major cause of patient distress. AD pathology is characterized by the deposition of extracellular Aβ peptides and by intraneuronal accumulation of hyperphosphorylated and aggregated tau protein [1]. Beside the pathological accumulation of intraneuronal neurofibrillary tangles and extracellular Aβ deposits, neurodegeneration and neuroinflammation associated with microgliosis and astrogliosis are prevalent in AD brains. In addition to the loss of cholinergic neurons, there is a significant loss of noradrenergic neurons in the locus coeruleus (LC) which may contribute to cognitive impairment and depression in AD [3]. GRK2 has been shown to result in tau hyperphosphorylation and is colocalized with neurofibrillary tangles in AD [5] suggesting that it may contribute to tau pathology in AD highlighting AR signaling and GRK2 modulation as valuable therapeutic targets for AD [4]
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