Immunotherapeutic approaches for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species.

Figure 1. Aβ and tau Conformational Changes in Alzheimer’s disease

1) Amyloid precursor protein (APP) undergoes normal cleavage by β and γ-secretase (presenilin [PS] is part of the γ-secretase complex) to produce the normal soluble Aβ (2). Soluble Aβ can undergo a conformational change to a β-sheet rich conformer (3) that further aggregates to form soluble, toxic Aβ oligomers. These may also precipitate to form relatively inert fibrils in amyloid plaques and congophilic amyloid angiopathy. A) Tau is a microtubule binding protein. Tau can undergo hyperphosphorylation (B) or a conformational change to a β-sheet conformer. These species can both further change to hyperphosphorylated tau in a β-sheet rich form (D) that is predisposed to further aggregation into toxic, tau oligomers. These can precipitate to form paired helical filaments (PHF) in the form (F) of neurofibrillary tangles. The Aβ β-sheet conformers and Aβ oligomers may cross seed, under some circumstances, with intermediate tau species in a β-sheet conformation and with tau oligomers (I and II), to synergistically exacerbate AD pathology. The most effective immunotherapeutic approaches for AD will need to be able to concurrently reduce levels of the toxic Aβ and tau oligomeric species.

Figure 2. Different Immunotherapeutic Approaches to Ameliorate AD Pathology

A) Active immunization can be performed using Aβ peptides, phosphorylated tau (ptau) peptides or preparations such as polymerized Bri peptide (pBri) as an immunogen. These immunogens are presented to B-cells by antigen presenting cells (APC). Use of Aβ peptides or ptau peptides will give rise to the production by B-cells of antibodies to Aβ or ptau epitopes, respectively. Use of pBri (or equivalent preparations of an immunogen that is a non-self peptide, in a stabilized, oligomeric β-sheet conformation) will lead to the production of antibodies that recognize both Aβ and tau pathological conformers (but not normal monomeric sAβ or tau proteins). B) Passive immunization can be performed by the production of monoclonal antibodies (mAb) that bind to Aβ, ptau or β-sheet pathological conformations. These antibodies need to be infused systemically in concentrations sufficient for adequate BBB penetration (typically only ~0.1% of a systemically injected mAb will cross the BBB). Once antibodies cross the BBB (using either active or passive immunization) they will act to enhance the clearance and degradation of their targets. Additional or alternative mechanisms may include disaggregation or neutralization of their target (i.e. blocking of toxicity). Abs to Aβ will recognize normal sAβ, oligomeric Aβ and/or deposited fibrillar Aβ (with varying preference depending on the type(s) of Abs to Aβ). Similarly, Abs to ptau will recognize monomeric ptau species, oligomeric tau and/or neurofibrillary tangles, with varying preference depending on the specific anti-ptau Ab(s). Abs to β-sheet will simultaneously act to ameliorate both Aβ and tau pathology by specifically binding pathological conformers; without binding to normal sAβ or tau. C) Stimulation of innate immunity can also be used to ameliorate AD pathology by enhancing microglia/macrophage function via Toll-like receptors (TLRs) or related pathways. Microglia/macrophages are stimulated similarly by the immune complexes produced using active or passive immunization approaches.