Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

The molecular pathology of Alzheimer's disease.

Tau protein isoforms, phosphorylation and role in neurodegenerative disorders

One hundred years ago a small group of psychiatrists described the abnormal protein deposits in the brain that define the most common neurodegenerative diseases Over the past 25 years, it has become clear that the proteins forming the deposits are central to the disease process Amyloid-β and tau make up the plaques and tangles of Alzheimer's disease, where these normally soluble proteins assemble into amyloid-like filaments Tau inclusions are also found in a number of related disorders Genetic studies have shown that dysfunction of amyloid-β or tau is sufficient to cause dementia The ongoing molecular dissection of the neurodegenerative pathways is expected to lead to a true understanding of disease pathogenesis

https://science.sciencemag.org/content/sci/314/5800/777.full.pdf

A Century of Alzheimer's Disease

The primal role that the amyloid-beta (Abeta) peptide has in the development of Alzheimer's disease is now almost universally accepted. It is also well recognized that Abeta exists in multiple assembly states, which have different physiological or pathophysiological effects. Although the classical view is that Abeta is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.

Intracellular amyloid-β in Alzheimer's disease

Antisera to paired helical filaments (PHF) were found to contain a significant amount of tau antibodies specific for a phosphorylated form, but only a negligible amount of those specific for a non-phosphorylated form. Also, the phosphorylated tau-specific antibodies, but not the non-phosphorylated tau-specific ones, labeled neurofibrillary tangles isolated in the presence of sodium dodecyl sulfate (SDS) and stained both tangles and senile plaque neuritis in fixed tissue sections in a very similar way to as the whole antiserum did. Taken together, these results strongly suggest that a major antigenic determinant of PHF is phosphorylated tau itself.

Phosphorylated Tau Protein Is Integrated into Paired Helical Filaments in Alzheimer's Disease

https://www.cell.com/neuron/pdf/0896-6273(88)90130-4.pdf

The carboxyl third of tau is tightly bound to paired helical filaments.

To determine the phosphorylation sites of the tau in paired helical filaments (PHF), two types of PHF antisera with different specificities were used: One was a conventional anti-PHF, and the other was an antiserum to formic acid-denatured PHF (anti-HFoPHF). Phosphorylated tau-specific antibodies, anti-ptau 1 and anti-ptau 2, were prepared from anti-PHF and anti-HFoPHF, respectively. We found that both anti-ptau 1 and anti-ptau 2 labeled fetal or juvenile tau but not adult tau. The anti-ptau 1- and anti-ptau 2-recognition sites were immunochemically localized to the fragment Asp313 to Ile328 in the most COOH-terminal portion of tau. Furthermore, Ser315 was determined as the anti-ptau 2 recognition site. The sequence surrounding Ser315 was not found in the canonical sequences phosphorylated with known kinases.

Fetal‐Type Phosphorylation of the τ in Paired Helical Filaments

The two antisera to paired helical filaments (PHF) and tau, which stained neu-rofibrillary tangles similarly in tissue section, were characterized. Anti-PHF reacted exclusively with the carboxyl terminal portion of tau, whereas antitau reacted with the amino terminal portion. In the blots of PHF prepared in Sarkosyl (Sarkosyl-PHF), anti-PHF stained an extensive smear from the top to the bottom of the gel, while antitau did not stain this kind of smear but labeled a small amount of intact tau that was bound to Sarkosyl-PHF. An LDS-or SDS-insoluble residue of Sarkosyl-PHF was labeled with anti-PHF, but not with antitau. Antitau-defined epitopes were susceptible to protease, whereas anti-PHF-defined epitopes were unaffected. Based on these observations, we conclude that Sarkosyl-PHF were composed largely of the carboxyl terminal region of tau and accompanied by a small amount of intact tau on their surfaces.

Reiko Miura

Papers

Phosphorylated Tau Protein Is Integrated into Paired Helical Filaments in Alzheimer's Disease

The carboxyl third of tau is tightly bound to paired helical filaments.

Fetal‐Type Phosphorylation of the τ in Paired Helical Filaments

Characterization of antisera to paired helical filaments and tau. Implication for the extent of tau tightly bound to paired helical filaments.

Selective determination of α2-plasmin inhibitor activity in plasma using chromogenic substrate