Molecular subtypes of Alzheimer’s disease

Abstract

Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer’s disease (AD), in which assemblies of amyloid β (Aβ) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that Aβ assemblies might have structural differences among AD brains and that such pleomorphic assemblies can correlate with distinct disease phenotypes. We found that in both sporadic and inherited forms of AD, amyloid aggregates differ in the biochemical composition of Aβ species. These differences affect the physicochemical properties of Aβ assemblies including aggregation kinetics, resistance to degradation by proteases and seeding ability. Aβ-amyloidosis can be induced and propagated in animal models by inoculation of brain extracts containing aggregated Aβ. We found that brain homogenates from AD patients with different molecular profiles of Aβ are able to induce distinct patterns of Aβ-amyloidosis when injected into mice. Overall these data suggest that the assembly of mixtures of Aβ peptides into different Aβ seeds leads to the formation of distinct subtypes of amyloid having distinctive physicochemical and biological properties which result in the generation of distinct AD molecular subgroups.

Prion-like propagation of β-amyloid aggregates in the absence of APP overexpression

“…Both Aβ aggregates purified from brains and Aβ aggregates formed from synthetic peptides can initiate Aβ deposition when inoculated into transgenic mice, and Aβ-injected animals exhibit electrophysiology and neurogenesis deficits as well as neuronal death [ 61 , 73 ]. Moreover, like prions, Aβ aggregates can exist as distinct strains with unique conformational properties that produce different pathological phenotypes upon injection into mice [ 13 , 15 , 28 , 47 , 60 , 68 ]. It has also been suggested that a prion-like transmission mechanism may explain the presence of cerebral Aβ pathology in individuals that have received human growth hormone treatments, dura mater grafts, or have undergone neurosurgery [ 10 , 16 , 20 , 23 , 30 , 32 , 33 , 49 ].…”

A distinct brain beta amyloid signature in cerebral amyloid angiopathy compared to Alzheimer’s disease

“…Αβ deposits in the brain can differ significantly between different conditions, such as pathological ageing [34] and AD [35]. Molecular subtypes of AD have also been reported, based on the relative abundance of observed Αβ peptides, each of which show different aggregation kinetics and resistance to degradation [36]. Hitherto, Αβ42 is one of the most well characterized diagnostic biomarkers for AD and it is well established that the concentration of Αβ42 is decreased in cerebrospinal fluid (CSF) from AD patients compared to healthy controls [37].…”

Unravelling the glial response in the pathogenesis of Alzheimer's disease

“…Over the last decade, some insights into the understanding of AD have come from studies of the prion diseases in which cell-to-cell transmission is achieved by templated misfolding of the normal protein substrate by the conformationally variant prion. AD is believed to exist in a number of subtypes, with experimental data indicating that different conformations of Ab and tau misfolded protein might underlie distinct pathologic phenotypes, a phenomenon possibly analogous to the multiple strains of the prion diseases (5)(6)(7)(8). In addition, the misfolded proteins in AD act as seeds for "prion-like" conversion of normally folded protein to abnormal conformations (9,10).…”