Developing Topics.

Background: Down syndrome (DS) is the most common and best-known chromosomal disorder in humans and the most frequent cause of intellectual disability of genetic origin, affecting about 6 million people worldwide. Individuals with DS may develop Alzheimer disease (AD) by age 55-60 years, and sometimes as young as 40 years due to the triplication of the amyloid β precursor protein (AβPP) gene, which is located on chromosome 21. The AD neuropathological phenotype in DS includes amyloid-β (Aβ) deposition (parenchymal and vascular) and neurofibrillary tangles comprised of tau protein.

Drug Development.

Background: VY-TAU01 is a recombinant humanized IgG4 monoclonal antibody (mAb) directed against pathological tau for the treatment of patients with mild dementia or mild cognitive impairment due to Alzheimer's disease (AD). Both VY-TAU01 and its parental mouse IgG1 mAb Ab-01 target an epitope in the C-terminus of tau, bind pathological tau with high affinity and selectivity over wild-type tau, block paired helical filament seed-induced tau aggregates in vitro, and selectively stain tau tangles in AD and P301S mouse (C57/B6J-Tg[Thy1-MAPT*P301S]2541Godt) brain. Ab-01 robustly inhibits seeding and propagation of pathological tau in a P301S mouse seeding model.

Comorbidities in early-onset sporadic versus presenilin-1 mutation-associated Alzheimer disease dementia: Evidence for dependency on Alzheimer disease neuropathological changes.

Studying comorbidities in early onset Alzheimer disease (AD) may provide an advantageous perspective on their pathogenesis because aging factors may be largely inoperative for these subjects. We compared AD comorbidities between early-onset sporadic cases and American and Colombian cases with PSEN1 mutations. AD neuropathological changes (ADNC) were very severe in all groups but more severe in the PSEN1 groups.

Dual-ligand fluorescence microscopy enables chronological and spatial histological assignment of distinct amyloid-β deposits.

Different types of deposits comprised of amyloid-β (Aβ) peptides are one of the pathological hallmarks of Alzheimer's disease (AD) and novel methods that enable identification of a diversity of Aβ deposits during the AD continuum are essential for understanding the role of these aggregates during the pathogenesis. Herein, different combinations of five fluorescent thiophene-based ligands were used for detection of Aβ deposits in brain tissue sections from transgenic mouse models with aggregated Aβ pathology, as well as brain tissue sections from patients affected by sporadic or dominantly inherited AD. When analyzing the sections with fluorescence microscopy, distinct ligand staining patterns related to the transgenic mouse model or to the age of the mice were observed.

Distinct Chemical Determinants are Essential for Achieving Ligands for Superior Optical Detection of Specific Amyloid-β Deposits in Alzheimer's Disease.

Aggregated forms of different proteins are common hallmarks for several neurodegenerative diseases, including Alzheimer's disease, and ligands that selectively detect specific protein aggregates are vital. Herein, we investigate the molecular requirements of thiophene-vinyl-benzothiazole based ligands to detect a specific type of Aβ deposits found in individuals with dominantly inherited Alzheimer's disease caused by the Arctic APP E693G mutation. The staining of these Aβ deposits was alternated when switching the terminal heterocyclic moiety attached to the thiophene-vinyl-benzothiazole scaffold.