Members of the group
Antibodies Specific for Amyloid ß Protofibrils - Strategy for Diagnostics and Therapeutics for Alzheimer's disease
The neuronal loss seen in patients suffering from Alzheimer's disease (AD) is probably due to aggregation of amyloid ß-peptide (Aß) in the brain. Due to its hydrophoicity, the Aß peptide self-aggregates and forms dimers, oligomers/protofibrils, and finally insoluble fibrils. These insoluble fibrils are the major component of the senile plaques which is a typical feature of an Alzheimer brain.
Accumulating evidence indicate that the soluble Aß protofibrils are responsible for the neurotoxicity in AD. For instance, it has been shown that levels of soluble Aß in brain are better correlated to dementia than amyloid plaque load and there are in vitro studies demonstrating that the protofibrils are neurotoxic.
The Arctic APP mutation (AßPP E693G), found in a Swedish family, is located within the Aß sequence and has been shown to enhance the formation of large soluble oligomers of Aß, i.e. protofibrils. This mutation further strengthens the theory of Aß protofibrils as being pathogenic in AD.
Our aim is to increase the knowledge of Aß protofibrils in the pathogenesis of Alzheimers disease. We have developed a monoclonal antibody selective for protofibrils, mAb158, to study its usefulness as a diagnostic marker for AD, both with imaging techniques such as Positron Emission Tomography (PET) and by biochemical assays in cerebrospinal fluid. mAb158 has also been tested as a therapeutics for AD in passive vaccination of transgenic mouse-models. The antibody has been humanized and named BAN2401, and is now in clinical trial for Alzheimer’s disease.
Boström G, Freyhult E, Virhammar J, Alcolea D, Tumani H, Otto M, Brundin RM, Kilander L, Löwenmark M, Giedraitis V, Lleó A, von Arnim CAF, Kultima K, Ingelsson M (2021). Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid. J Alzheimers Dis. 81: 629-640.
Khoonsari PE, Shevchenko G, Herman S, Remnestal J, Giedraitis V, Brundin R, Degerman Gunnarsson M, Kilander L, Zetterberg H, Nilsson P, Lannfelt L, Ingelsson M and Kultima K (2019). Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers. J Alzheimers Dis. 67: 639-651.
Velickaite V, Giedraitis V, Strom K, Alafuzoff I, Zetterberg H, Lannfelt L, Kilander L, Larsson EM and Ingelsson M (2017). Cognitive function in very old men does not correlate to biomarkers of Alzheimer's disease. BMC Geriatr. 17: 208.
Degerman Gunnarsson M, Ingelsson M, Blennow K, Basun H, Lannfelt L and Kilander L (2016). High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease. Alzheimers Res Ther. 8: 22.
Basun H, Bogdanovic N, Ingelsson M, Almkvist O, Naslund J, Axelman K, Bird TD, Nochlin D, Schellenberg GD, Wahlund LO and Lannfelt L (2008). Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol. 65: 499-505.
Englund H, Sehlin D, Johansson AS, Nilsson LN, Gellerfors P, Paulie S, Lannfelt L and Pettersson FE (2007). Sensitive ELISA detection of amyloid-beta protofibrils in biological samples. J Neurochem. 103: 334-45.
Stenh C, Nilsberth C, Hammarback J, Engvall B, Naslund J and Lannfelt L (2002). The Arctic mutation interferes with processing of the amyloid precursor protein. Neuroreport. 13: 1857-60.
Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J and Lannfelt L (2001). The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 4: 887-93.
Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B and Lannfelt L (1992). A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1: 345-7.