Modeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease

Abstract

Patients suffering from Alzheimer's disease (AD) are typified and diagnosed postmortem by the combined accumulations of extracellular amyloid plaques and of intracellular tauopathy, consisting of neuropil treads and neurofibrillary tangles in the somata. Both hallmarks are inseparable and remain diagnostic as described by Alois Alzheimer more than a century ago. Nevertheless, these pathological features are largely abandoned as being the actual pathogenic or neurotoxic factors. The previous, almost exclusive experimental attention on amyloid has shifted over the last 10 years in two directions. Firstly, from the “concrete” deposits of amyloid plaques to less well-defined soluble or pseudosoluble oligomers of the amyloid peptides, ranging from dimers to dodecamers and even larger aggregates. A second shift in research focus is from amyloid to tauopathy, and to their mutual relation. The role of Tau in the pathogenesis and disease progression is appreciated as leading to synaptic and neuronal loss, causing cognitive deficits and dementia. Both trends are incorporated in a modified amyloid cascade hypothesis, briefly discussed in this paper that is mainly concerned with the second aspect, that is, protein Tau and its associated fundamental questions.

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

“…The AAV-based model, therefore, is most complementary to the existing transgenic mouse models, which largely lack the neurodegeneration and inflammation aspects for as yet unknown reasons. 4,5 The data further validate the AAV-based model for mechanisms that underlie tau-induced neurodegeneration downstream of the amyloid connection in AD and are relevant in primary tauopathies.…”

“…1 This model robustly recapitulates neurodegeneration in vivo, which is largely lacking in transgenic mouse models of amyloidopathy and tauopathy. 4,5,9,10 We observed that protein tau, present in an apparent oligomeric state, effected cellular demise via non-apoptotic mechanisms, and a large panel of markers implicated inflammation as a major actor. 1 The third major defect in AD-affected brain, neuroinflammation, was thereby implicated in the novel AAV-based model.…”

“…The relative timing and molecular relation between amyloid and tauopathies are still debated, whereas the link to kinases such as GSK3␤ is becoming accepted. [1][2][3][4][5] Although aggregation of phosphorylated protein tau into filamentous inclusions in soma and neuropil is characteristic and diagnostic of all tauopathies, the neurotoxic phosphorylated tau species that damages synapses and neurons remains elusive. By analogy to amyloids, it is not the final tau deposits but the intermediate tau oligomers that were first suspected to cause disease; however, their cellular sites of action and the mechanisms whereby neurons succumb in tauopathy remain to be defined.…”

β2 Adrenergic Receptor, Protein Kinase A (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models

“…Genetic data have implied that deranged tau-microtubule interactions induced either by phosphorylation or increased levels of tau, contribute to or even are sufficient to cause synaptic and dendritic degeneration in primary tauopathies (35)(36)(37). It has been reported that transfection of tau in mature neurons leads to an improper distribution of tau into the somatodendritic compartment with concomitant degeneration of synapses, as seen by the disappearance of spines and presynaptic and postsynaptic markers (3,7).…”

Effects of antibodies to phosphorylated and non-phosphorylated tau on in vitro tau phosphorylation at Serine-199: Preliminary report

“…The significance of NFT formation is unclear. Soluble oligomers are thought to be tau's most neurotoxic conformation (Jaworski et al, 2010), so NFT formation may play a neuroprotective role by sequestering these oligomers (Spires-Jones et al, 2011).…”