AD's tangled tail

Abstract

A Cleveland Clinic group has created a mouse model of Alzheimer's disease that bridges the mechanistic gap between two key disease-related proteins: amyloid-β (A4) precursor protein and tau. 1 The surprise is that the mice develop the disease phenotype independently of β-amyloid, the extracellular fragment of amyloid-β (A4) precursor protein that many believe to be the prime suspect in Alzheimer's disease.Instead, the disease in these mice appears to be caused by an intracellular fragment of amyloid-β (A4) precursor protein (APP) that goes on to trigger both abnormal hyperphosphorylated microtubule-associated protein-τ (MAPT; FTDP-17; tau) phosphorylation and neuronal death-two hallmarks of human AD that are not seen in the most widely used mouse models.The model thus raises fresh doubts about whether β-amyloid (Aβ) is really the cause of pathology and instead points to the intracellular portion of APP as the real culprit in AD.Aβ is a byproduct of proteolytic processing of APP that accumulates on the outside of cells in amyloid plaques. Aβ is toxic to neurons and is often detected in the serum and brains of AD patients.Another characteristic feature of AD brains is the presence of intracellular tangles of tau.Because commonly used mouse models of AD do not fully reproduce the abnormalities seen in the brains of AD patients, researchers have debated which of the two proteins is more important in pathology."The standard AD models aren't doing what they should do," said Donna Wilcock, assistant professor of neurology at Duke University School of Medicine.Building on previous hints about the Aβ-independent effects of APP in cell culture, a team led by Sanjay Pimplikar, assistant staff member at the Cleveland Clinic, created knock-in mice that overexpress the intracellular domain of APP. These mice developed an ADlike syndrome without developing plaques, suggesting that plaques per se are not needed for disease.After 18 months, mice overexpressing the APP intracellular domain had hippocampal neuron loss and modest memory deficits compared with controls. The transgenic mice also had high levels of hyperphosphorylated tau."The dominant hypothesis of Aβ as a causative agent may not be enough" to explain the paper's findings, said Pimplikar. "We have recapitulated most of the key features of the disease with just the intracellular APP fragment. These mice don't have any additional Aβ-this shows that you don't need Aβ to have the disease."Pimplikar's team also found that treating the mice with lithium chloride prevented memory problems compared with no treatment. Lithium inhibits glycogen synthase kinase 3β (GSK3B), a kinase that phosphorylates tau. 2 Pimplikar thus thinks the intracellular domain of APP activates GSK3B, which leads to tau phosphorylation and ultimately to neurodegeneration. He told SciBX that his findings could cut Aβ out of the picture as a causative factor in AD.He also believes blocking the ability of the intracellular APP fragment to stimulate tau hyperphosphorylation may help halt AD progression....