The MAPT gene, located on chromosome 17 arm 21, consists of 16 exons. Exons 1, 4, 5, 7, and 13, along with 9, 11, and 12, are consistently transcribed in the central nervous system (CNS). This gene gives rise to six different isoforms, ranging from 45 to 65 kDa. In a healthy adult brain, equal amounts of 4R to 3R tau isoforms are observed but this ratio varies in tauopathies. Conditions like AD and non-Alzheimer's tauopathy like frontotemporal dementia with parkinsonism are classified as mixed 3R and 4R tauopathies. Tau isoforms exhibit also differences in aggregation properties. (B) The 29 amino acids sequences in the N-terminal portion of Tau are followed by a basic proline-rich region. This N-terminal part known as the projection domain potentially interacts with other elements of the cytoskeleton and plasma membrane. The C-terminal section, referred to as the repeat domains (R1-R4), comprise three (3R) or four copies (4R) of a highly conserved sequence of 18 amino acids. The microtubule-binding region is involved in microtubule assembly. 13 (C) The PTMs are distributed throughout the entire protein chain and are critical drivers of Tau aggregation. This technology proved invaluable for the preparation of N-acylurea (MeNbz) thioester surrogates directly from SPPS. While generally effective, certain cases revealed an incompatibility between the peptide chain and the activation step of MeNbz. To circumvent this, an alternative thioester strategy was adopted using the acid-sensitive HMPB linker resin, which selectively detached protected C-terminal acids from the resin with diluted TFA in CH2Cl2. Furthermore, we utilized acyl hydrazides, instrumental in their subsequent conversion into thioesters. Bocprotected Dbz linkers were employed for the synthesis of C-terminal Dbz residues, which can be converted into acyl-benzotriazoles using NaNO2 acting as hydrazide substitutes. Additionally, some segments, specifically Tau (41-76) and Tau(119-156), contained aspartimide-prone aspartic acid-glycine sequences, which could be effectively suppressed with the aid of DMB-protected dipeptides. 84