**5.4 Neuroprotective function in additional neurological diseases**

Apart from ischemia, trauma, or tumors, deafferentation and neurodegeneration also induce TGF-β expression in the central nervous system (Morgan et al., 1993). Therefore, it is not surprising that TGF-βs were implicated in a variety of neurodegenerative diseases.

Alzheimer's disease (AD) is characterized by the presence of amyloid (Abeta) plaques, neurofibrillary tangles, and neuronal loss. The disorder is also frequently associated with cerebrovascular changes, including perivascular astrocytosis, amyloid deposition, and microvascular degeneration, but it is not known whether these pathological changes contribute to functional deficits in AD. TGF-β1 expressed in the astrocytes of transgenic mice induced a prominent perivascular astrocytosis, followed by the accumulation of basement membrane proteins in microvessels, thickening of capillary basement membranes, and later, around 6 months of age, deposition of amyloid in cerebral blood vessels. At 9 months of age, various AD-like degenerative alterations were observed in endothelial cells and pericytes. These results suggest that chronic overproduction of TGF-β1 triggers a pathogenic cascade leading to AD-like cerebrovascular amyloidosis, microvascular degeneration, and local alterations in brain metabolic activity (Wyss-Coray et al., 2000). A specific impairment of TGF-β1 signaling pathway has also been demonstrated in AD brain. The deficiency of TGF-β1 signaling has been shown to increase both Abeta accumulation and Abeta-induced neurodegeneration in AD models. The loss of function of TGF-β pathway also seems to contribute to tau pathology and neurofibrillary tangle formation (Caraci et al., 2009). Growing evidence suggests a neuroprotective role for TGF-β1 against Abeta toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF-β1 levels in the central nervous system. The combined Abeta- and TGF-β1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring Abeta and TGF-β1 increments (Ongali et al., 2011). Thus, TGF-β1 might be considered as new neuroprotective tools against Abeta-induced neurodegeneration.

A defective expression or activity of neurotrophic factors, such as brain- and glial-derived neurotrophic factors, is known to contribute to neuronal damage in Huntington's disease (HD). Asymptomatic HD patients also showed a reduction in TGF-β1 levels in the peripheral blood, which was related to trinucleotide mutation length and glucose hypometabolism in the caudate nucleus. Immunohistochemical analysis in post-mortem brain tissues showed that TGF-β1 was reduced in cortical neurons in HD patients. In mouse models of HD, the animals showed a reduced expression of TGF-β1 in the cerebral cortex, localized in neurons, but not in astrocytes. In these mice, glutamate receptor agonist failed to increase TGF-β1 formation in the cerebral cortex and corpus striatum, suggesting that a defect in the regulation of TGF-β1 production is associated with HD. Accordingly, reduced TGF-β mRNA and protein levels were found in cultured astrocytes transfected with mutated exon 1 of the human huntingtin gene, and in striatal knock-in cell lines expressing full-length huntingtin with an expanded glutamine repeat (Battaglia et al., 2011). These data suggest that serum TGF-β1 levels are potential biomarkers of HD development during the asymptomatic phase of the disease, and raise the possibility that strategies aimed at rescuing TGF-β1 levels in the brain may influence the progression of HD.

Additional neurodegenerative diseases were also associated with an alteration of the TGFβs. Using immunohistochemistry, the expression of TGF-β2 appeared in neurofibrillary tangle bearing neurons and tangle-bearing glial cells in progressive supranuclear palsy and in neurons with age-related neurofibrillary tangle formation (Lippa et al., 1995). Widespread staining of reactive astrocytes for TGF-β2 was observed in all degenerative diseases. TGF-β1 and -3 staining was not selectively altered in these diseases (Lippa et al., 1995). These data suggest that the induction of TGF-β2 may be an intrinsic part of the processes that underlie neurofibrillary tangle formation and reactive gliosis in a variety of neurodegenerative diseases.

Activation of the TGF-β pathway was identified as the underlying mechanism behind the epileptogenic effect of albumin following the compromise of the blood brain barrier (Cacheaux et al., 2009). TGF-β1 resulted in epileptiform activity similar to that after exposure to albumin. Coimmunoprecipitation revealed binding of albumin to TGF-β receptor II, and Smad2 phosphorylation confirmed downstream activation of this pathway. Transcriptome profiling demonstrated similar expression patterns after blood brain barrier breakdown, albumin, and TGF-β1 exposure, including modulation of genes associated with the TGF-β pathway, early astrocytic activation, inflammation, and reduced inhibitory transmission. Importantly, TGF-β pathway blockers suppressed most albumin-induced transcriptional changes and prevented the generation of epileptiform activity. Based on these data, the TGF-β pathway was suggested to be a novel putative epileptogenic signaling cascade and therapeutic target for the prevention of injury-induced epilepsy (Cacheaux et al., 2009).
