The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation.
María Pagnon de la VegaVilmantas GiedraitisWojciech MichnoLena KilanderGokhan GunerMara ZielinskiMalin LöwenmarkRoseMarie BrundinTorsten DanforsLinda SöderbergIrina AlafuzoffLars N G NilssonAnna ErlandssonDieter WillboldStephan A MüllerGunnar F SchröderJörg HanriederStefan F LichtenthalerLars LannfeltDag SehlinMartin IngelssonPublished in: Science translational medicine (2021)
Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the Uppsala APP mutation (Δ690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aβ42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing β-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aβ, AβUpp1-42Δ19-24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.
Keyphrases
- early onset
- positron emission tomography
- cerebrospinal fluid
- mass spectrometry
- computed tomography
- resting state
- case report
- cognitive decline
- late onset
- white matter
- stem cells
- functional connectivity
- copy number
- depressive symptoms
- cell therapy
- dna methylation
- blood brain barrier
- physical activity
- pet ct
- brain injury
- sleep quality
- protein protein
- capillary electrophoresis