Aβ and Tau Conformational Changes in AD
(1–5) (1) APP undergoes normal cleavage by β and γ-secretase (PS is part of the γ-secretase complex) to produce the (2) normal sAβ. sAβ can undergo a conformational change to (3) a β sheet-rich conformer that further aggregates to form (4) soluble, toxic Aβ oligomers. These also may precipitate to form (5) relatively inert fibrils in amyloid plaques and congophilic amyloid angiopathy.
(A–F) (A) Tau is a microtubule-binding protein. Tau can undergo (B) hyperphosphorylation or (C) a conformational change to a β sheet conformer. These species can both further change to (D) hyperphosphorylated tau in a β sheet-rich form that is predisposed to further aggregation into (E) toxic, tau oligomers. These can precipitate to form (F) PHFs in the form of NFTs.
(I and II) 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, 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.
Different Immunotherapeutic Approaches to Ameliorate AD Pathology
(A) Active immunization can be performed using Aβ peptides, phosphorylated tau (ptau) peptides, or preparations such as 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 mAbs 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). Antibodies to Aβ will recognize normal sAβ, oligomeric Aβ, and/or deposited fibrillar Aβ (with varying preference depending on the type[s] of antibodies to Aβ). Similarly, antibodies to ptau will recognize monomeric ptau species, oligomeric tau, and/or NFTs, with varying preference depending on the specific anti-ptau antibody(ies). Antibodies to β sheet will simultaneously act to ameliorate both Aβ and tau pathologies by specifically binding pathological conformers, without binding to normal sAβ or tau.
(C) Stimulation of innate immunity also can be used to ameliorate AD pathology by enhancing microglia/macrophage function via TLRs or related pathways. Microglia/macrophages are stimulated similarly by the immune complexes produced using active or passive immunization approaches.