The immunological recognition pattern of one of the most commonly used monoclonal antibodies, PHF-1, which detects the paired helical filaments of Alzheimer's disease, exhibits a high degree of similarity with the recognition of a polyclonal antibody, anti-T3P, raised against a synthetic phosphopeptide, GAEIVYKS(Phospho)PVVSGD, corresponding to amino acids 389-402 of the microtubule-associated protein tau. A panel of 16 synthetic non-phosphorylated and phosphorylated peptides, excised from different regions of tau and peptide analogs thereof, were used to show that PHF-1 is indeed directed against the T3 fragment. Circular dichroism spectroscopy shows that the phosphorylated peptide exhibits a limited propensity to form intramolecular beta-pleated sheets, and alteration is found in the reverse-turn structure that dominates the middle section of the molecule. The shift in the turn-forming amino acids may also allow a stacking procedure, may interfere with microtubule assembly, and, consequently, may be accountable for deposit formation.