Impact of APOE genotype on prion-type propagation of tauopathy

Abstract

Apolipoprotein (APOE) is a major risk factor of Alzheimer’s disease (AD), with the E2, E3 and E4 isoforms differentially regulating the burden of AD-associated neuropathologies, such as amyloid β and tau. In AD, pathological tau is thought to spread along neuroanatomic connections following a prion-like mechanism. To provide insights into whether APOE isoforms differentially regulate the prion properties of tau and determine trans-synaptic transmission of tauopathy, we have generated human P301S mutant tau transgenic mice (PS19) that carry human APOE (APOE2, APOE3 or APOE4) or mouse Apoe allele. Mice received intrahippocamal injections of preformed aggregates of K18-tau at young ages, which were analyzed 5 months post-inoculation. Compared to the parental PS19 mice with mouse Apoe alleles, PS19 mice expressing human APOE alleles generally responded to K18-tau seeding with more intense AT8 immunoreactive phosphorylated tau athology. APOE3 homozygous mice accumulated higher levels of AT8-reactive ptau and microgliosis relative to APOE2 or APOE4 homozygotes (E3 > E4~2). PS19 mice that were heterozygous for APOE3 showed similar results, albeit to a lesser degree. In the timeframe of our investigation, we did not observe significant induction of argentophilic or MC1-reactive neurofibrillary tau tangle in PS19 mice homozygous for human APOE. To our knowledge, this is the first comprehensive study in rodent models that provides neuropathological insights into the dose-dependent effect of APOE isoforms on phosphorylated tau pathology induced by recombinant tau prions.

Shaping the future of preclinical development of successful disease-modifying drugs against Alzheimer's disease: a systematic review of tau propagation models

“…The CA1 and entorhinal cortex (EC) regions heavily innervate the subiculum, which is one of the major sources of efferent projections from the hippocampal formation. In line with this far-reaching network of hippocampal connections, the CA regions [ 1 , 4 , 7 , 11 , 15 , 19 , 30 , 32 , 45 , 48 , 49 , 58 , 67 , 69 , 71 , 75 , 80 , 96 , 109 , 115 , 116 , 120 , 123 , 138 , 140 , 144 , 146 , 155 , 161 , 162 , 173 ], DG [ 1 , 7 , 11 , 15 , 32 , 49 , 58 , 67 , 69 , 71 , 75 , 80 , 109 , 115 , 120 , 123 , 138 , 142 , 146 , 173 ], the fimbria [ 4 , 7 , 11 , 19 , 29 , 30 , 32 , 45 , 48 , 49 , 67 – 69 , 71 , 115 , 120 ], the entorhinal cortex (EC)...…”

“…Synthetic PFFs, have played a pivotal role in demonstrating that tau-aggregation and propagation can be induced by altered tau alone, independent of other proteins, underscoring the role of pathologically altered tau as the causative agent. These fibrils were meticulously characterized and were composed of recombinantly produced full-length (T40) [ 58 , 67 , 75 , 76 , 164 ] or truncated (K18, K19, dGAE) tau [ 4 , 75 , 123 , 144 , 155 , 162 , 173 ], either as wild type [ 76 , 162 , 164 , 173 ] or with mutations (P301S [ 4 , 58 , 75 , 123 , 144 , 155 ], P301L [ 75 , 76 , 103 ] or C291S[ 164 ]). They were assembled into fibrillary aggregates using polyanionic inducers such heparin [ 4 , 58 , 67 , 75 , 76 , 103 , 123 , 133 , 144 , 155 , 162 , 164 , 173 ].…”

“…These fibrils were meticulously characterized and were composed of recombinantly produced full-length (T40) [ 58 , 67 , 75 , 76 , 164 ] or truncated (K18, K19, dGAE) tau [ 4 , 75 , 123 , 144 , 155 , 162 , 173 ], either as wild type [ 76 , 162 , 164 , 173 ] or with mutations (P301S [ 4 , 58 , 75 , 123 , 144 , 155 ], P301L [ 75 , 76 , 103 ] or C291S[ 164 ]). They were assembled into fibrillary aggregates using polyanionic inducers such heparin [ 4 , 58 , 67 , 75 , 76 , 103 , 123 , 133 , 144 , 155 , 162 , 164 , 173 ]. Aggregation confirmation was obtained through Thioflavin T assay [ 4 , 67 , 75 , 76 , 103 , 155 ], or TEM [ 4 , 67 , 76 , 144 , 155 , 164 , 173 ].…”

“…The hippocampus emerged as the preferred site of tau inoculation across the majority of studies [ 1 , 4 , 10 , 11 , 15 , 19 , 29 , 30 , 32 , 45 , 48 , 49 , 58 , 67 , 69 , 74 , 75 , 80 , 96 , 109 , 116 , 123 , 144 , 146 , 157 , 161 , 162 , 173 ]. This preference is rooted in the understanding that the neurofibrillary pathology in the AD brain initiates within the hippocampus, subsequently propagating sequentially to the limbic system and ultimately reaching the isocortex [ 21 ].…”

Chemotherapy promotes astrocytic response to Aβ deposition, but not Aβ levels, in a mouse model of amyloid and APOE

“…There are appropriate mouse models to test whether chemotherapy increases tau accumulation with overexpression of mutant tau in the presence of APOE3 or APOE4. These models show adverse effects of APOE4 on tau phosphorylation and misfolding ( Jablonski et al, 2021 ), on tau propagation ( Williams et al, 2022 ), and on brain atrophy and neurodegeneration ( Shi et al, 2017 ). Analyses of these models could test whether chemotherapy affected tau accumulation in an APOE-dependent manner, as we have done here for Aβ.…”