{"doi":"10.4103/nrr.nrr-d-24-00699","title":"Misfolded amyloid-beta conformational variants (strains) as drivers of Alzheimer’s disease neuropathology","abstract":"Pathological and clinical variability in Alzheimer’s disease (AD): AD is clinically characterized by progressive memory loss and cognitive impairment. From a pathological point of view, the main features of AD are the deposition of amyloid plaques (composed of amyloid-beta, Aβ) and neurofibrillary tangles containing hyperphosphorylated Tau in the brain, accompanied by neuronal and synaptic loss, neuroinflammation and brain atrophy (Jellinger, 2022). Regardless of these common traits, growing evidence shows increased heterogeneity in the brain of AD patients considering both clinical manifestations and pathological features. Mounting evidence points to the variable conformations that misfolded Aβ can acquire (referred to as “Aβ strains”) as the source of this pathological and clinical variability. The existence of Aβ strains is relevant as they may also predict prognosis and responses to treatments. The concept of Aβ strains is analogous to that coined for infectious prion strains, which are further defined below (Jellinger, 2022). Prion strains: The term prion defines proteinaceous infectious particles referred to as PrPSc (Morales, 2017). Prions are responsible for several neurodegenerative diseases, known as transmissible spongiform encephalopathies (Morales, 2017). Notably, prions lack nucleic acids, therefore their disease-associated properties are encoded in the three-dimensional structure of these infectious proteins (Morales, 2017). Prions have the unique characteristic of recruiting monomers of the normally folded protein (PrPC), inducing the formation of additional PrPSc units (Morales, 2017). Importantly, PrPSc can transfer its disease-associated features to either other cells, tissues, or individuals (Morales, 2017). It has been documented that prions, associated with Creutzfeldt-Jakob Disease in humans have been inadvertently transmitted to healthy individuals through medical procedures such as corneal transplants, implantation of electrodes and cadaveric-human growth hormone administrations (Gomez-Gutierrez and Morales, 2020). Prions are known to exist in different “strains,” concept that encompasses the variable pathological and biochemical properties induced by a specific prion agent, as well as the clinical manifestations induced by them in the host (Morales, 2017). Different prion strains have been identified within the same animal species (Morales, 2017). The criteria used to differentiate and classify prion strains are mainly based on their biochemical and biological properties (Morales, 2017). Nonetheless, the main difference between strains lies in the different conformations of PrPSc that are faithfully retained and propagated (Morales, 2017). In humans, different polymorphisms in the prion protein have been identified, thus leading to the formation of different strains. These prion strains are linked with specific neuropathological and clinical manifestations (Morales, 2017). Interestingly, different prion strains can be sustained within the same aminoacidic sequence (Morales, 2017). The presence of diverse prion strains has led scientists to hypothesize that other aggregation-prone proteins, such as Aβ, α-synuclein, and Tau also display conformational strain variations. This may explain the heterogenous phenotypes reported for AD, and other tauopathies and synucleinopathies (Gomez-Gutierrez and Morales, 2020). Aβ strains—prion-like behavior and molecular features: Aβ is generated by the sequential cleavage of the transmembrane protein amyloid precursor protein (APP), which is sequentially processed by two enzymes called β- and γ-secretases: the action of the latter leads to the production of fragments between 39 and 43 amino acids (Heilbronner et al., 2013). Two of these fragments, either 40 or 42 amino acids long and known as Aβ40 or Aβ42, respectively, are the most studied: Aβ40 is the most abundant form, while Aβ42 is considered the most relevant in disease (Heilbronner et al., 2013). Each one of the","journal":"Neural Regeneration Research","year":2024,"id":507943,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":292757,"name":"Rodrigo Morales","orcid":"0000-0001-7766-5770","position":1,"is_corresponding":false},{"id":1359693,"name":"Salvatore Saieva","orcid":"0000-0001-9586-6920","position":0,"is_corresponding":true}],"reference_count":14,"raw_metadata":null,"created_at":"2026-07-19T02:11:06.395600Z","pmid":"39715091","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}