Neuropathology and biochemistry of early onset familial Alzheimer’s disease caused by presenilin-1 missense mutation Thr116Asn

Abstract

The majority (~ 55%) of early onset familial Alzheimer disease (FAD) is caused by mutations in the presenilin 1 gene (PSEN1). Here, we describe a family with early onset FAD with a missense mutation in the PSEN1 gene (Thr116Asn). Five family members developed dementia in the third decade of life. One subject underwent autopsy. The onset of clinical symptoms was at the age of 37 years and the disease progressed rapidly. The clinical picture was characterised by progressive memory impairment, amnestic aphasia, and gait disturbances. Neuropathological assessment revealed widespread β-amyloid (Thal phase 5) and tau (Braak stage 6) pathology. Abundant deposition of diffuse and cored plaques was distributed in cortical and subcortical areas, as well as in the cerebellum, while cotton wool plaques were observed mainly in the occipital cortex. Cerebral amyloid angiopathy was present throughout the brain. In the neocortex, tau pathology, especially neuropil threads, was more abundant in the frontal and occipital cortex and in the hippocampus. Proteomic analyses revealed that the pattern of sarkosyl-insoluble tau was similar to the one seen in sporadic AD. No α-synuclein or TDP-43 pathology was found either in cortical nor in subcortical areas. Here, we present the first comprehensive neuropathological and biochemical study of early onset FAD with a missense mutation Thr116Asn in the presenilin 1 gene. In contrast to other PS1-linked AD patients, the present subject developed cotton wool plaques which were not associated with spastic paraparesis.

Therapeutic antibody targeting microtubule-binding domain prevents neuronal internalization of extracellular tau via masking neuron surface proteoglycans

“…The sarkosyl-insoluble 2p tau fractions were also isolated from human AD brain tissue using the same procedure as described above. Human brain samples (transentorhinal cortex, NFTs rich Braak stage VI, AD sporadic and AD familial with a missense mutation of PSEN1 (Thr116Asn) [85]) were obtained from Newcastle Brain Bank and Slovak Brain Bank in accordance with ethical approval.…”

“…Truncated tau (297–391/4R) and human brain-derived AD tau (transentorhinal cortex from two sporadic AD patients and one familial AD case [85], both NFT rich Braak stage VI) fluorescently labelled with Alexa Fluor 488 or Alexa Fluor 594 were diluted in neuronal conditioned media at the concentration corresponding to 100–200 nM for monomeric tau protein in combination with the following antibodies: unrelated control antibody DC51 [56], mouse monoclonal DC8E8 (mDC8E8), humanized DC8E8 (AX004/IgG1; AX004/IgG4) and their isotype controls IgG1/IgG4 (BioLegend), all of concentration of 1 μM and incubated for 30 min at 37 °C. Pre-formed tau-antibody complexes were added to neurons for 24 h. For experiments where heparin was used (Tinzaparin sodium, Sigma-Aldrich, which is a LMWH), fluorescently labelled tau aggregates were preincubated with heparin (5 μM) for 30 min and heparin-AD tau complexes were applied to neurons for 16–20 h. Neurons were washed three times with pre-warmed PBS, followed by mild trypsinisation (0.06% trypsin-EDTA 2–3 min) to remove cell surface bound tau and dissociate neurons into single cells.…”

Gene mutations in a Han Chinese Alzheimer's disease cohort

“…The early-onset AD (EOAD) refers to the age of disease onset <65 years, encompassing about 4%-6% of all the AD cases (Mendez, 2017). On the other hand, late-onset AD (LOAD), which is the most common form, occurs in individuals >65 years of age (Sutovsky et al, 2018). Generally, AD is considered to be a polygenic disease resulting from complex interactions between environmental factors and several genes (Che et al, 2018).…”

“…Generally, AD is considered to be a polygenic disease resulting from complex interactions between environmental factors and several genes (Che et al, 2018). Reportedly, the three common causative genes associated with AD include the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes (Sutovsky et al, 2018). However, some rare frontotemporal lobar degeneration (FTLD) mutations in genes such as progranulin (GRN), C9orf72, and microtubule-associated protein tau (MAPT) have also been described in clinical AD cohorts or families with AD clinical phenotypes (Piccoli et al, 2016).…”

Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer’s Disease with APP Osaka Mutation

“…Cerebellar lesions with senile plaques and/or neurofibrillary tangles as well as Purkinje cell loss were pathologically reported in some FAD patients [ 20 , 21 , 22 , 23 ], whereas these pathological changes were usually not found until the end stage in SAD [ 24 ]. In the present study, Aβ and tau accumulation in the cerebellum were only found in FAD (Osaka).…”