Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer's disease

Abstract

Growing evidence suggests that amyloid beta (Aβ) and tau pathologies are strongly associated with mitochondrial dysfunction and neuronal damage in Alzheimer's disease (AD). Extensive research of AD postmortem brains, mouse and fly models, including triple transgenic AD mice and mutant tau mice, and cell culture studies revealed that tau hyperphosphorylation is caused by multiple factors, including intraneuronal Aβ-oligomers, chronic oxidative stress, reduced insulin-like growth factor 1, and astrocytic mediated-Aβ and caspase activation. Overexpressed and phosphorylated tau appears to impair axonal transport of organelles causing synapse starvation, depletion of ATP, and ultimately neuronal damage. This article evaluates the role of tau in mitochondrial dysfunction and assesses how hyperphosphorylated tau impairs axonal transport of organelles in AD neurons.

Figure 1

Illustration represents human tau gene. Six isoforms are generated by alternative splicing of 2, 3 and 10 exons in human tau gene.

Figure 2

Possible factors that induce hyperphosphorylation of tau. 1. Aβ-mediated caspase activation, 2. Aβ-mediated oxidative stress, 3. Chronic oxidative stress, 4. Reduced IGF1-mediated oxidative stress and 5. Mutations in tau gene.

Figure 3

Schematic representation of axonal transport of organelles in neurons A. represents neuron from control subject and B. represents neuron from Alzheimer’s disease patient. In healthy neuron, tau protein binds tightly to microtubule and allow normal axonal transport of organelles, including mitochondria and axonal transport of organelles is impaired in AD neuron because of destabilization hyperphosphorylated tau to microtubules.

Figure 4

N-terminal tau and Aβ peptide association with mitochondria and causes abnormal mitochondrial dynamics, mitochondrial dysfunction and neuronal damage.