ABSTRACT
The role of hyperphosphorylation of tau in Alzheimer's disease is still unsolved. Here we describe a novel transgenic mouse model, expressing a pseudohyperphosphorylated (PHP) variant of the longest human CNS tau isoform in forebrain neurons. We report that pseudohyperphosphorylation decreases phosphorylation at T205 while other sites (T212, S262) are less or not affected compared to mice expressing wildtype tau. Despite the differences in phosphorylation, the subcellular distribution of tau is not affected and mice do not develop highly aggregated states of tau. PHP tau expressing mice do not show any evidence for neurodegeneration as determined from morphometric measurements of neocortical regions, caspase activation, analysis of mitochondrial dysfunction, or determination of spine densities. In agreement, no differences in learning and memory are observed. The data indicates that moderate levels of modified tau alone are not sufficient to induce tau aggregation or neurodegeneration in transgenic mice. With our model it becomes possible to study the effects of hyperphosphorylation at conditions which may prevail in an early preaggregation state of the disease.
Subject(s)
Nerve Degeneration/metabolism , Nerve Degeneration/pathology , tau Proteins/genetics , tau Proteins/metabolism , Age Factors , Animals , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Minisatellite Repeats/genetics , Nerve Degeneration/genetics , Neurons/metabolism , Neurons/ultrastructure , Phosphorylation/genetics , Prosencephalon/pathology , Protein Binding/genetics , Silver Staining/methods , Sulfate Adenylyltransferase/metabolismABSTRACT
Classic neurotransmitter phenotypes are generally predetermined and develop as a consequence of target-independent lineage decisions. A unique mode of target-dependent phenotype instruction is the acquisition of the cholinergic phenotype in the peripheral sympathetic nervous system. A body of work suggests that the sweat gland plays an important role to determine the cholinergic phenotype at this target site. A key issue is whether neurons destined to innervate the sweat glands express cholinergic markers before or only after their terminals make target contact. We employed cholinergic-specific over-expression of the vesicular acetylcholine transporter (VAChT) in transgenic mice to overcome sensitivity limits in the detection of initial cholinergic sweat gland innervation. We found that VAChT immunoreactive nerve terminals were present around the sweat gland anlage already from the earliest postnatal stages on, coincident selectively at this sympathetic target with tyrosine hydroxylase-positive fibers. Our results provide a new mechanistic model for sympathetic neuron-target interaction during development, with initial selection by the target of pioneering nerve terminals expressing a cholinergic phenotype, and subsequent stabilization of this phenotype during development.
