ubule associated protein important for the stability of axonal microtubules. Tau hyperphosphorylation impairs its binding to microtubules, changing the trafficking route for molecules which may ultimately lead to synaptic degeneration (13, 14). Diabetes induces tau hyperphosphorylation in the brain, as for example in the hippocampus (15), and proteolytic tau cleavage (16), being both processes occuring in Alzheimer’s disease (17). Hyperglycemia and insulin dysfunction may induce tau modifications, and therefore may play a role for the increased incidence of Alzheimer’s disease in diabetic patients (16). Tau modification impairs axonal transport through microtubule arrangement disruption and by blocking axonal trafficking route, which can culminate in synaptic function changes and consequent neurodegeneration (18, 19). In Alzheimer’s disease, glycation of tau may stabilize paired helical filaments aggregation leading to tangle formation (20). It is likely that similar processes may be occuring under diabetes.

Neurofilaments

Neurofilaments (NF) are the intermediate filaments (10 nm) found specifically in neurons that assemble from three subunits based on molecular weight: NF-L (70 kDa), NF-M (150 kDa), and NF-H (200 kDa) (21). Neurofilaments lack overall polarity upon assembly and mainly provide neuronal structural stabilization and regulate axonal growth (22). Aggregation of neurofilaments is a common marker of neurodegenerative diseases (23). Abnormal NF expression, processing, and structure may contribute to diabetic neuropathy, since reduced synthesis of NF proteins or formation of incorrectly associated NFs could severely disrupt the axonal cytoskeleton (24).

Neurofilament mRNAs are selectively reduced in diabetic rats and alterations on post-translational modification of NF proteins have been detected. A reduction of myelinated fiber size is correlated with axonal NFs loss in peripheral nerves of STZ-induced diabetic rats (25, 26), and mRNAs levels encoding for NF-L and NF-H are reduced in the same animal model of diabetes (7). Moreover, changes on the expression of several NF-associated protein kinases isoforms may also contribute to diabetes-induced changes (4). Several protein kinases regulate NF phosphorylation status, being NFs hyperphosphorylation a hallmark of several neurodegenerative diseases. Abnormal NF phosphorylation has been described in sensory neurons of anim