Phosphoproteomics of Alzheimer disease brain: Insights into altered brain protein regulation of critical neuronal functions and their contributions to subsequent cognitive loss

Abstract

Alzheimer disease (AD) is the major locus of dementia worldwide. In the USA there are nearly 6 million persons with this disorder, and estimates of 13-20 million AD cases in the next three decades. The molecular bases for AD remain unknown, though processes involving amyloid beta-peptide as small oligomeric forms are gaining attention as known agents to both lead to oxidative stress and synaptic dysfunction associated with cognitive dysfunction in AD and its earlier forms, including amnestic mild cognitive impairment (MCI) and possibly preclinical Alzheimer disease (PCAD). Altered brain protein phosphorylation is a hallmark of AD, and phosphoproteomics offers an opportunity to identify these altered phosphoproteins in order to gain more insights into molecular mechanisms of neuronal dysfunction and death that lead to cognitive loss. This paper reviews what, to this author, are believed to be the known phosphoproteomics studies related to in vitro and in vivo models of AD as well as phosphoproteomics studies of brains from subjects with AD, and in at least one case in MCI and PCAD as well. The results of this review are discussed with relevance to new insights into AD brain protein dysregulation in critical neuronal functions and to potential therapeutic targets to slow, or in favorable cases, halt progression of this dementing disorder that affects millions of persons and their families worldwide.

Keywords: Alzheimer disease; Cognitive loss; Phosphoproteomics; Protein dysregulation.

Fig. 1.

Phosphorylation of Ser, Thr, or Tyr residues on proteins regulates the function of these proteins due to electrostatic effects. In most cases in biochemistry, function changes if structure changes. Upper Figure: Phosphorylation of Ser located near a negatively charge amino acid (shown here Glu) puts two negatively charged species in close proximity that leads to their repulsion and consequent alterations of the 3-dimensional structure of the protein and consequent change in function. Lower Figure: Similar considerations apply but in this case phosphorylation occurs in close proximity to a positively charged amino acid (shown here Lys) that causes attraction of these two oppositely charged residues, again with changes in the 3-dimensional structure of the protein and consequent change in function.