Cholinergic and inflammatory phenotypes in transgenic tau mouse models of Alzheimer's disease and frontotemporal lobar degeneration.

An early and sizeable loss of basal forebrain cholinergic neurons is a well-characterized feature associated with measurable deficits in spatial learning and cognitive impairment in patients with Alzheimer's disease. In addition, pro-inflammatory glial cells such as astrocytes and microglia may play a key role in the neurodegenerative cascade of Alzheimer's disease and tauopathies. We recently presented two mouse models: Line 1, expressing the truncated tau fragment identified as the core of the Alzheimer's paired helical filament, and Line 66, expressing full-length human tau carrying a double mutation (P301S and G335D). Line 1 mice have a pathology that is akin to Alzheimer's, whilst Line 66 resembles frontotemporal lobar degeneration. However, their cholinergic and inflammatory phenotypes remain elusive. We performed histological evaluation of choline acetyltransferase, acetylcholinesterase, p75 neurotrophin receptor, microglial ionized calcium binding adaptor molecule 1 and astrocytic glial fibrillary acidic protein in the basal forebrain, hippocampus and cortex of these models. A significant lowering of choline acetyltransferase-positive neurons and p75-positive neurons in the basal forebrain of Line 1 at 3, 6 and 9 months was observed in two independent studies, alongside a significant decrease in acetylcholinesterase staining in the cortex and hippocampus. The reductions in choline acetyltransferase positivity varied between 30% and 50% at an age when Line 1 mice show spatial learning impairments. Furthermore, an increase in microglial ionized calcium binding adaptor molecule 1 staining was observed in the basal forebrain, hippocampus and entorhinal cortex of Line 1 at 6 months. Line 66 mice displayed an intact cholinergic basal forebrain, and no difference in p75-positive neurons at 3 or 9 months. In addition, Line 66 exhibited significant microglial ionized calcium binding adaptor molecule 1 increase in the basal forebrain and hippocampus, suggesting a prominent neuroinflammatory profile. Increased concentrations of microglial interleukin-1ß and astrocytic complement 3 were also seen in the hippocampus of both Line 1 and Line 66. The cholinergic deficit in Line 1 mice confirms the Alzheimer's disease-like phenotype in Line 1 mice, whilst Line 66 revealed no measurable change in total cholinergic expression, a phenotypic trait of frontotemporal lobar degeneration. These two transgenic lines are therefore suitable for discriminating mechanistic underpinnings between the Alzheimer's and frontotemporal lobar degeneration-like phenotypes of these mice.

Dangerous Liaisons: Tau Interaction with Muscarinic Receptors.

The molecular processes underlying neurodegenerative diseases (such as Alzheimer's Disease - AD) remain poorly understood. There is also an imperative need for disease-modifying therapies in AD since the present treatments, acetylcholinesterase inhibitors and NMDA antagonists, do not halt its progression. AD and other dementias present unique pathological features such as that of microtubule associated protein tau metabolic regulation. Tau has numerous binding partners, including signaling molecules, cytoskeletal elements and lipids, which suggests that it is a multifunctional protein. AD has also been associated with severe loss of cholinergic markers in the brain and such loss may be due to the toxic interaction of tau with cholinergic muscarinic receptors. By using specific antagonists of muscarinic receptors it was found in vitro that extracellular tau binds to M1 and M3 receptors and which the increase of intracellular calcium found in neuronal cells upon tau-binding. However, so far, the significance of tau signaling through muscarinic receptor in vivo in tauopathic models remains uncertain. The data reviewed in the present paper highlight the significant effect of M1 receptor/tau interaction in exacerbating tauopathy related pathological features and suggest that selective M1 agonists may serve as a prototype for future therapeutic development toward modification of currently intractable neurodegenerative diseases, such as tauopathies.

BDNF as a Promising Therapeutic Agent in Parkinson's Disease.

Brain-derived neurotrophic factor (BDNF) promotes neuroprotection and neuroregeneration. In animal models of Parkinson's disease (PD), BDNF enhances the survival of dopaminergic neurons, improves dopaminergic neurotransmission and motor performance. Pharmacological therapies of PD are symptom-targeting, and their effectiveness decreases with the progression of the disease; therefore, new therapeutical approaches are needed. Since, in both PD patients and animal PD models, decreased level of BDNF was found in the nigrostriatal pathway, it has been hypothesized that BDNF may serve as a therapeutic agent. Direct delivery of exogenous BDNF into the patient's brain did not relieve the symptoms of disease, nor did attempts to enhance BDNF expression with gene therapy. Physical training was neuroprotective in animal models of PD. This effect is mediated, at least partly, by BDNF. Animal studies revealed that physical activity increases BDNF and tropomyosin receptor kinase B (TrkB) expression, leading to inhibition of neurodegeneration through induction of transcription factors and expression of genes related to neuronal proliferation, survival, and inflammatory response. This review focuses on the evidence that increasing BDNF level due to gene modulation or physical exercise has a neuroprotective effect and could be considered as adjunctive therapy in PD.

Exercise-Induced Neuroprotection and Recovery of Motor Function in Animal Models of Parkinson's Disease.

Parkinson's disease (PD) is manifested by progressive motor, autonomic, and cognitive disturbances. Dopamine (DA) synthesizing neurons in the substantia nigra (SN) degenerate, causing a decline in DA level in the striatum that leads to the characteristic movement disorders. A disease-modifying therapy to arrest PD progression remains unattainable with current pharmacotherapies, most of which cause severe side effects and lose their efficacy with time. For this reason, there is a need to seek new therapies supporting the pharmacological treatment of PD. Motor therapy is recommended for pharmacologically treated PD patients as it alleviates the symptoms. Molecular mechanisms behind the beneficial effects of motor therapy are unknown, nor is it known whether such therapy may be neuroprotective in PD patients. Due to obvious limitations, human studies are unlikely to answer these questions; therefore, the use of animal models of PD seems indispensable. Motor therapy in animal models of PD characterized by the loss of dopaminergic neurons has neuroprotective and neuroregenerative effects, and the completeness of neuronal protection may depend on (i) degree of neuronal loss, (ii) duration and intensity of exercise, and (iii) time elapsed between insult and commencing of training. As the physical activity is neuroprotective for dopaminergic neurons, the question arises what is the mechanism of this protective action. A current hypothesis assumes a central role of neurotrophic factors in the neuroprotection of dopaminergic neurons, even though it is still not clear whether increased DA level in the nigrostriatal axis results from neurogenesis of dopaminergic neurons in the SN, recovery of the phenotype of dopaminergic neurons, increased sprouting of the residual dopaminergic axons in the striatum, or generation of local striatal neurons from inhibitory interneurons. In the present review, we discuss studies describing the influence of physical exercise on the PD-like changes manifested in animal models of the disease and focus our interest on the current state of knowledge on the mechanism of neuroprotection induced by physical activity as a supportive therapy in PD.

Is senescence-associated ß-galactosidase a marker of neuronal senescence?

One of the features of cellular senescence is the activity of senescence-associated- ß-galactosidase (SA-ß-gal). The main purpose of this study was to evaluate this marker of senescence in aging neurons. We found that cortical neurons exhibited noticeable SA-ß-gal activity quite early in culture. Many SA-ß-gal-positive neurons were negative for another canonical marker of senescence, namely, double-strand DNA breaks (DSBs). Moreover, DDR signalling triggered by low doses of doxorubicin did not accelerate the appearance of neuronal SA-ß-gal. In vivo, we observed pronounced induction of SA-ß-gal activity in the hippocampus of 24-month-old mice, which is consistent with previous findings and supports the view that at this advanced age neurons developed a senescence-like phenotype. Surprisingly however, relatively high SA-ß-gal activity, probably unrelated to the senescence process, was also observed in much younger, 3-month-old mice. In conclusion, we propose that SA-ß-gal activity in neurons cannot be attributed uniquely to cell senescence either in vitro or in vivo. Additionally, we showed induction of REST protein in aging neurons in long-term culture and we propose that REST could be a marker of neuronal senescence in vitro.