Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease

Abstract

The microtubule-associated protein Tau is a major component of the neurofibrillary tangles that serve as a neuropathological hallmark of Alzheimer's disease. Tau is a substrate for protein phosphorylation at multiple sites and occurs in tangles in a hyperphosphorylated state. However, the physiological functions of Tau phosphorylation or how it may contribute mechanistically to Alzheimer's pathophysiology are not completely understood. Here, we examined the function of human Tau phosphorylation at three sites, Ser199, Ser202, and Thr205, which together comprise the AT8 sites that mark abnormal phosphorylation in Alzheimer's disease. Overexpression of wild-type Tau or mutated forms in which these sites had been changed to either unphosphorylatable alanines or phosphomimetic aspartates inhibited mitochondrial movement in the neurite processes of PC12 cells as well as the axons of mouse brain cortical neurons. However, the greatest effects on mitochondrial translocation were induced by phosphomimetic mutations. These mutations also caused expansion of the space between microtubules in cultured cells when membrane tension was reduced by disrupting actin filaments. Thus, Tau phosphorylation at the AT8 sites may have meaningful effects on mitochondrial movement, likely by controlling microtubule spacing. Hyperphosphorylation of the AT8 sites may contribute to axonal degeneration by disrupting mitochondrial transport in Alzheimer's disease.

Isomerase Pin1 Stimulates Dephosphorylation of Tau Protein at Cyclin-dependent Kinase (Cdk5)-dependent Alzheimer Phosphorylation Sites

“…The binding of Pin1 to Tau at the Alzheimer-related phosphorylation site AT8, whose epitope is generated by phosphorylation of Tau at sites including Ser-202 and Thr-205 (55,56), has been reported recently in rat cortical neurons (57); this finding is consistent with our present results. However, we do not know why these sites were not detected as Pin1-binding sites in previous work.…”

Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027

“…Tau phosphorylation helps determine the spacing between microtubules, and so alterations could influence the transport of larger cargo, such as mitochondria (Shahpasand et al, 2012), significantly impacting neuronal function through changes in ATP availability. Tau mislocalization has been associated with disruption of neurofilament structure, loss of dendritic spines (Zempel and Mandelkow, 2011), and alterations in AMPA receptor trafficking (Hoover et al, 2010).…”

Deciphering the mechanism underlying late-onset Alzheimer disease

“…24 Such changes might cause the protein extrusion mechanism to decline or fail completely, thereby inducing focal axonal swellings and concomitant accumulation of mitochondria and other organelles ( Figure 1, step 3). 25,26 Disturbed energy metabolism in the axon could induce further tau phosphorylation, 27 an additional neuropathological event that probably facilitates the formation of paired helical filaments (PHFs; precursor elements of neurofibrillary tangles), as seen in doubleimmune-challenged mice. 17 This outcome would lead to further impairments in axonal transport, complete transport blockade, and ultimately axonal leakage ( Figure 1, step 4; Figure 2a).…”