Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Abstract

The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

Doxycycline interferes with tau amyloid aggregation abolishing its associated neuronal toxicity

“…The surface hydrophobicity of tau aggregates has been associated with both cellular toxicity and their ability to serve as nucleation seeds for monomers [54]. Interaction of hydrophobic aggregated species with cell membranes, which induces permeability and ultimately dysfunction, is thought to be the mechanism responsible for toxicity [35,55,56].…”

Monoclonal Antibodies as Neurological Therapeutics

“…The lack of clear proof of efficacy of Aβ targeting therapies so far has raised skepticism regarding the validity of the amyloid hypothesis, driving researchers to explore tau pathology as a plausible therapeutic target, particularly as cognitive decline in AD exhibits a better correlation with tau accumulation than with Aβ deposition [ 218 , 219 , 220 , 221 ]. Monoclonal antibodies targeting abnormal forms of tau protein and particularly soluble oligomers which appear to be the most neurotoxic form of p -tau [ 222 ] are being explored for efficacy in AD. To date, gosuranemab, zagotenemab, tilavonemab, and semorinemab are in Phase II trials of prodromal to mild AD [ 130 ].…”

Polyphenols from Brown Seaweeds (Ochrophyta, Phaeophyceae): Phlorotannins in the Pursuit of Natural Alternatives to Tackle Neurodegeneration

“…Hence, Aβ formation can be hindered by targeting these secretases, which can help to delay or stop the progression of AD. The tau hypothesis acknowledges that intracellular deposits of hyperphosphorylated microtubule-associated tau protein are toxic to neurons and highly correlated with the cognitive deficits observed not only in AD but also in other neurodegenerative disorders [ 6 ]. The direct inhibition of tau aggregation has been suggested as one approach for potentially reversing neurofibrillary lesion formation [ 7 ].…”