Vaccination as a therapeutic approach to Alzheimer's disease

Abstract

Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid beta peptide is converted into oligomeric/fibrillar amyloid beta. The oligomeric forms of amyloid beta have been hypothesized to be the most toxic, whereas fibrillar amyloid beta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid beta-related and tau-related pathologies.

Figure 1

Shows a schematic representation of the human tau gene which is located on chromosome 17q21, and spans more than 130 kb. This gene is composed of 16 Exons. (A). Exons 1 and 14 are transcribed but not translated (turquoise color). The Exons 4A, 6 and 8 are not transcribed in human (light blue/charcoal color) (B). In the human brain, 6 tau isoforms ranging from 352 to 441 amino acids are generated by alternative splicing of Exons 2, 3, and 10 (shown in brown/red, pink and red respectively) from a single gene. Exons 1, 4, 5, 7, 9, 11, 12 and 13 (blue color) are included in all isoforms. Exon 3 is always included with Exon 2. The microtubule binding domains are indicated by R1, R2, R3 and R4, which correspond respectively to Exon 9, 10, 11 and 12, respectively. (C). Extraction of tau proteins and PHF-Tau from normal and Alzheimer brain respectively, shows by immunoblotting six bands between 45-68 kDa which correspond to different tau isoform in normal brain, while in PHF-tau 4 bands are detected between 60-74 KDa which corresponds to the aggregation of 6 hyperphosphorylated tau isoforms in the AD brain.

Figure 2

Shows the electrophoresis of RT-PCR amplification products of the 5’ domain of tau mRNAs (A), of the 3’ domain of tau mRNAs (B). Extraction of RNA was performed in from the cerebellar cortex of a sporadic Alzheimer’s disease patient. The expression of mRNA by RT-PCR shows different isoforms of human tau detected in the N-terminal (0N, 1N, 2N) and in the C-terminal (3R, 4R). Symbol (+) indicates with exon, while (-) indicates without exon.

Figure 3

In the human Alzheimer brain, more than 40 phosphorylation sites on tau have been identified and localized in the proline-rich domain and in the C-terminal region. Phosphorylated sites are identified with 8 phospho-tau specific antibodies as indicated in figure.1C, with a red color. It has been suggested that the phosphorylation at Ser 262/356 is responsible for the detachment of tau from microtubules.