Hyperacetylation mimetics within the tau filament core inhibits prion-like propagation of misfolded tau.

Acetylation of key Lysine residues characterizes aggregates of the microtubule-associated protein tau constituting the neuropathological hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). This has led to the idea that acetylation influences tau aggregation. Using a HEK293 cell-based aggregation assay, we tested whether acetylation-mimicking substitutions (K→Q) on five AD-associated acetyl-modified sites (AcK-311, 353, 369, 370, 375) influenced its propensity to aggregate when exposed to tau seeds derived from two clinically distinctive diseases - AD and PSP. In combination, the presence of 5K→Q sites ablated tau aggregation induced by seeds from both AD and PSP patients, indicating that acetylation within the filament core domain of tau could have an inhibitory effect on seed-mediated aggregation. We had previously identified that a phosphorylation-mimetic on Ser305 (S→E) abrogated tau aggregation by seeds from AD patients, without affecting seeding by PSP patients. Combining the S305→E to the 5K→Q acetyl-modified sites, we found that this tau could now be seeded only by PSP patients, but not by AD patients, confirming Ser305 as a critical determinant of strain-specific tau seeding. On the other hand, acetylation-nullifying substitutions (K→R or K→A) on these same Lys sites did not alter tau seeding abilities compared to the parental tau construct. Notably, the combined acetylation-nullifying Alanine substitutions on these 5 Lys sites resulted in spontaneous self-aggregation, with the filaments resembling amorphous deposits. All together, we demonstrate that cooperative acetyl-occupancy in the tau filament core influences seeded propagation of misfolded tau as well as drives self-aggregation.

Aß Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer's Disease.

We report a highly significant correlation in brain proteome changes between Alzheimers disease (AD) and CRND8 APP695NL/F transgenic mice. However, integrating protein changes observed in the CRND8 mice with co-expression networks derived from human AD, reveals both conserved and divergent module changes. For the most highly conserved module (M42, matrisome) we find many proteins accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of A ß ; in plaques and in CAA; further, recombinant MDK and PTN enhance A ß ; aggregation into amyloid. Multiple M42 proteins, annotated as heparan sulfate binding proteins, bind to fibrillar A ß 42 and a non-human amyloid fibril in vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart and islet amyloid polypeptide (IAPP) amyloid in the pancreas. Our findings establish several critical insights. Proteomic changes in modules observed in human AD brains define an A ß ; amyloid responsome that is well conserved from mouse model to human. Further, distinct amyloid structures may serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions. We hypothesize that this co-accumulation may contribute to downstream pathological sequalae. Overall, this contextualized understanding of proteomic changes and their interplay with amyloid deposition provides valuable insights into the complexity of AD pathogenesis and potential biomarkers and therapeutic targets.

Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau.

Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer's disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical residues determine templated tau seeding. Our initial data with phosphorylation-ablating mutations (Ser/Thr → Ala) on select sites of P301L tau showed no changes in seeding efficacy by AD-tau or PSP-tau. Interestingly, when specific sites in the R1-R2 repeat domains (Ser262/Thr263/Ser289/Ser305) were mutated to phosphorylation-mimicking amino acid Glu, it substantially reduced the seeding efficiency of AD-tau, but not PSP-tau seeds. The resultant detergent-insoluble tau shows deficient phosphorylation on AT8, AT100, AT180 and PHF1 epitopes, indicating inter-domain cooperativity. We further identify Ser305 as a critical determinant of AD-tau-specific seeding, whereby the phospho-mimicking Ser305Glu tau abrogates seeding by AD-tau but not PSP-tau. This suggests that phosphorylation on Ser305 could be related to the formation of disease-specific tau strains. Our results highlight the existence of a phospho-PTM code in tau seeding and further demonstrate the distinctive nature of this code in 4R tauopathies.

Multiple Factors Influence the Incubation Period of ALS Prion-like Transmission in SOD1 Transgenic Mice.

Mutations in superoxide dismutase 1 (SOD1) that are associated with amyotrophic lateral sclerosis (ALS) cause its misfolding and aggregation. Prior studies have demonstrated that the misfolded conformation of ALS-SOD1 can template with naïve SOD1 "host proteins" to propagate, spread, and induce paralysis in SOD1 transgenic mice. These observations have advanced the argument that SOD1 is a host protein for an ALS conformer that is prion-like and experimentally transmissible. Here, we investigated the propagation of different isolates of G93A-SOD1 ALS conformers using a paradigm involving transmission to mice expressing human G85R-SOD1 fused to yellow fluorescent protein (G85R-SOD1:YFP). In these studies, we also utilized a newly developed line of mice in which the G85R-SOD1:YFP construct was flanked by loxp sites, allowing its temporal and spatial regulation. We used methods in which the G93A ALS conformers were injected into the sciatic nerve or hindlimb muscle of adult transgenic mice. We observed that the incubation period to paralysis varied significantly depending upon the source of inoculum containing misfolded G93A SOD1. Serial passage and selection produced stable isolates of G93A ALS conformers that exhibited a defined minimum incubation period of ~2.5 months when injected into the sciatic nerve of young adult mice. As expected, neuronal excision of the transgene in loxpG85R-SOD1:YFP mice blocked induction of paralysis by transmission of G93A ALS conformers. Our findings indicate that G93A ALS conformers capable of inducing disease require neuronal expression of a receptive host SOD1 protein for propagation, with a defined incubation period to paralysis.

Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy.

Apolipoprotein (APOE) E4 isoform is a major risk factor of Alzheimer's disease and contributes to metabolic and neuropathological abnormalities during brain aging. To provide insights into whether APOE4 genotype is related to tau-associated neurodegeneration, we have generated human P301S mutant tau transgenic mice (PS19) that carry humanized APOE alleles (APOE2, APOE3 or APOE4). In aging mice that succumbed to paralysis, PS19 mice homozygous for APOE3 had the longest lifespan when compared to APOE4 and APOE2 homozygous mice (APOE3 > APOE4 ~ APOE2). Heterozygous mice with one human APOE and one mouse Apoe allele did not show any variations in lifespan. At end-stage, PS19 mice homozygous for APOE3 and APOE4 showed equivalent levels of phosphorylated tau burden, inflammation levels and ventricular volumes. Compared to these cohorts, PS19 mice homozygous for APOE2 showed lower induction of phosphorylation on selective epitopes, though the effect sizes were small and variable. In spite of this, the APOE2 cohort showed shorter lifespan relative to APOE3 homozygous mice. None of the cohorts accumulated appreciable levels of phosphorylated tau compartmentalized in the insoluble cell fraction. RNAseq analysis showed that the induction of immune gene expression was comparable across all the APOE genotypes in PS19 mice. Notably, the APOE4 homozygous mice showed additional induction of transcripts corresponding to the Alzheimer's disease-related plaque-induced gene signature. In human Alzheimer's disease brain tissues, we found no direct correlation between higher burden of phosphorylated tau and APOE4 genotype. As expected, there was a strong correlation between phosphorylated tau burden with amyloid deposition in APOE4-positive Alzheimer's disease cases. Overall, our results indicate that APOE3 genotype may confer some resilience to tauopathy, while APOE4 and APOE2 may act through multiple pathways to increase the pathogenicity in the context of tauopathy.

Modeling the Competition between Misfolded Aß Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer's Disease.

The amyloid pathology characteristic of Alzheimer's disease (AD) can be broadly classified as either fibrillary amyloid or diffuse amyloid. Fibrillary amyloid is found in cored-neuritic deposits, fibrillar deposits, and vascular deposits, and binds strongly to the amyloid revealing dyes Thioflavin-S or Congo Red. Diffuse amyloid can appear as wispy dispersed deposits or compact tufted deposits dispersed in neuropil, and binds amyloid dyes weakly if at all. In AD brains, both types of pathology are detected. Homogenates from AD brains, or the brains of transgenic mice modeling AD-amyloidosis, have been used to seed pathology in vulnerable host transgenic models. These studies suggest that pathologies may arise from distinct conformers or strains of misfolded Aß, similar to propagating prions. Using Aß strains sourced from four different AD-amyloidosis models, we injected pathological seeds into the brains of newborn mice from three different transgenic hosts with distinctive Aß pathologies. Two of the seeding sources were from mice that primarily develop cored-neuritic Aß deposits (cored strain) while the other two seeding sources were from mice that develop diffuse Aß deposits (diffuse strain). These seeds were injected into host APP mice in which the resident strain was either diffuse or cored-neuritic pathology. Seeding-homogenates were injected into the brains of newborn mice to initiate propagation as early as possible. Depending upon the level of transgene expression in the host, we show that the injected strains of misfolded Aß from the seeding homogenate were able to outcompete the resident strain of the APP host model. In serial passaging experiments, it appeared that the diffuse strain was more easily propagated than the cored strain. Collectively, our studies align with the idea that different types of Aß pathology in AD brains arise from different populations of Aß conformers that compete to populate the brain.

Soluble brain homogenates from diverse human and mouse sources preferentially seed diffuse Aß plaque pathology when injected into newborn mouse hosts.

Background: Seeding of pathology related to Alzheimer's disease (AD) and Lewy body disease (LBD) by tissue homogenates or purified protein aggregates in various model systems has revealed prion-like properties of these disorders. Typically, these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could direct the evolution of amyloid-ß (Aß) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in susceptible mouse models. Methods: Homogenates of human pre-frontal cortex were injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aß pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. For comparison, homogenates of aged APP transgenic mice that preferentially exhibit diffuse or cored deposits were similarly injected into the brains of newborn APP mice. Results: We observed that lysates from the brains with AD (Aß+, tau+), AD/LBD (Aß+, tau+, αSyn+), or Pathological Aging (Aß+, tau-, αSyn-) efficiently seeded diffuse Aß deposits. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Performance in fear-conditioning cognitive tasks was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Homogenates prepared from aged APP transgenic mice with diffuse Aß deposits induced similar deposits in APP host mice; whereas homogenates from APP mice with cored deposits induced similar cored deposits, albeit at a lower level. Conclusions: These findings are consistent with the idea that diffuse Aß pathology, which is a common feature of human AD, AD/LBD, and PA brains, may arise from a distinct strain of misfolded Aß that is highly transmissible to newborn transgenic APP mice. Seeding of tau or αSyn comorbidities was inefficient in the models we used, indicating that additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice.

Pathogenic tau recruits wild-type tau into brain inclusions and induces gut degeneration in transgenic SPAM mice.

Pathological tau inclusions are neuropathologic hallmarks of many neurodegenerative diseases. We generated and characterized a transgenic mouse model expressing pathogenic human tau with S320F and P301S aggregating mutations (SPAM) at transgene levels below endogenous mouse tau protein levels. This mouse model develops a predictable temporal progression of tau pathology in the brain with biochemical and ultrastructural properties akin to authentic tau inclusions. Surprisingly, pathogenic human tau extensively recruited endogenous mouse tau into insoluble aggregates. Despite the early onset and rapid progressive nature of tau pathology, major neuroinflammatory and transcriptional changes were only detectable at later time points. Moreover, tau SPAM mice are the first model to develop loss of enteric neurons due to tau accumulation resulting in a lethal phenotype. With moderate transgene expression, rapidly progressing tau pathology, and a highly predictable lethal phenotype, the tau SPAM model reveals new associations of tau neurotoxicity in the brain and intestinal tract.

Impact of APOE genotype on prion-type propagation of tauopathy.

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 ß 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.

Blood-based biomarkers of inflammation in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease in which many processes are detected including (neuro)inflammation. Many drugs have been tested for ALS in clinical trials but most have failed to reach their primary endpoints. The development and inclusion of different types of biomarkers in diagnosis and clinical trials can assist in determining target engagement of a drug, in distinguishing between ALS and other diseases, and in predicting disease progression rate, drug responsiveness, or an adverse event. Ideally, among other characteristics, a biomarker in ALS correlates highly with a disease process in the central nervous system or with disease progression and is conveniently obtained in a peripheral tissue. Here, we describe the state of biomarkers of inflammation in ALS by focusing on peripherally detectable and cellular responses from blood cells, and provide new (combinatorial) directions for exploration that are now feasible due to technological advancements.

TAPPing into the potential of inducible tau/APP transgenic mice.

AIMS: Our understanding of the pathological interactions between amyloidosis and tauopathy in Alzheimer's disease is incomplete. We sought to determine if the relative timing of the amyloidosis and tauopathy is critical for amyloid-enhanced tauopathy. METHODS: We crossed an inducible tauopathy model with two ß-amyloid models utilising the doxycycline-repressible transgenic system to modulate timing and duration of human tau expression in the context of amyloidosis and then assessed tauopathy, amyloidosis and gliosis. RESULTS: We combined inducible rTg4510 tau with APPswe/PS1dE9 [Line 85 (L85)] mice to examine the interactions between Aß and tauopathy at different stages of amyloidosis. When we initially suppressed mutant human tau expression for 14-15 months and subsequently induced tau expression for 6 months, severe amyloidosis with robust tauopathy resulted in rTg4510/L85 but not rTg4510 mice. When we suppressed mutant tau for 7 months before inducing expression for a subsequent 6 months in another cohort of rTg4510/L85 and rTg4510 mice, only rTg4510/L85 mice displayed robust tauopathy. Lastly, we crossed rTg4510 mice to tet-regulated APPswe/ind [Line 107 (L107)] mice, using doxycycline to initially suppress both transgenes for 1 month before inducing expression for 5 months to model early amyloidosis. In contrast to rTg4510, rTg4510/L107 mice rapidly developed amyloidosis, accompanied by robust tauopathy. CONCLUSIONS: These data suggest that tau misfolding is exacerbated by both newly forming Aß deposits in younger brain and mature deposits in older brains. Refined use and repurposing of these models provide new tools to explore the intersection of ageing, amyloid and tauopathy and to test interventions to disrupt the amyloid cascade.

Collusion of α-Synuclein and Aß aggravating co-morbidities in a novel prion-type mouse model.

BACKGROUND: The misfolding of host-encoded proteins into pathological prion conformations is a defining characteristic of many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Lewy body dementia. A current area of intense study is the way in which the pathological deposition of these proteins might influence each other, as various combinations of co-pathology between prion-capable proteins are associated with exacerbation of disease. A spectrum of pathological, genetic and biochemical evidence provides credence to the notion that amyloid ß (Aß) accumulation can induce and promote α-synuclein pathology, driving neurodegeneration. METHODS: To assess the interplay between α-synuclein and Aß on protein aggregation kinetics, we crossed mice expressing human α-synuclein (M20) with APPswe/PS1dE9 transgenic mice (L85) to generate M20/L85 mice. We then injected α-synuclein preformed fibrils (PFFs) unilaterally into the hippocampus of 6-month-old mice, harvesting 2 or 4 months later. RESULTS: Immunohistochemical analysis of M20/L85 mice revealed that pre-existing Aß plaques exacerbate the spread and deposition of induced α-synuclein pathology. This process was associated with increased neuroinflammation. Unexpectedly, the injection of α-synuclein PFFs in L85 mice enhanced the deposition of Aß; whereas the level of Aß deposition in M20/L85 bigenic mice, injected with α-synuclein PFFs, did not differ from that of mice injected with PBS. CONCLUSIONS: These studies reveal novel and unexpected interplays between α-synuclein pathology, Aß and neuroinflammation in mice that recapitulate the pathology of Alzheimer's disease and Lewy body dementia.

Astrocytic apoE4 and tau: Deadly combination for neurons.

New data from Wang and colleagues1 suggest that astrocyte-derived apoE4 drives tau-mediated neurodegeneration. This research highlights how a genetic risk factor for Alzheimer's disease is a major determinant of neurodegeneration in tau-expressing neurons by regulating non-cell-autonomous pathways.

Variation in the vulnerability of mice expressing human superoxide dismutase 1 to prion-like seeding: a study of the influence of primary amino acid sequence.

Misfolded forms of superoxide dismutase 1 (SOD1) with mutations associated with familial amyotrophic lateral sclerosis (fALS) exhibit prion characteristics, including the ability to act as seeds to accelerate motor neuron disease in mouse models. A key feature of infectious prion seeding is that the efficiency of transmission is governed by the primary sequence of prion protein (PrP). Isologous seeding, where the sequence of the PrP in the seed matches that of the host, is generally much more efficient than when there is a sequence mis-match. Here, we used paradigms in which mutant SOD1 seeding homogenates were injected intraspinally in newborn mice or into the sciatic nerve of adult mice, to assess the influence of SOD1 primary sequence on seeding efficiency. We observed a spectrum of seeding efficiencies depending upon both the SOD1 expressed by mice injected with seeds and the origin of the seed preparations. Mice expressing WT human SOD1 or the disease variant G37R were resistant to isologous seeding. Mice expressing G93A SOD1 were also largely resistant to isologous seeding, with limited success in one line of mice that express at low levels. By contrast, mice expressing human G85R-SOD1 were highly susceptible to isologous seeding but resistant to heterologous seeding by homogenates from paralyzed mice over-expressing mouse SOD1-G86R. In other seeding experiments with G85R SOD1:YFP mice, we observed that homogenates from paralyzed animals expressing the H46R or G37R variants of human SOD1 were less effective than seeds prepared from mice expressing the human G93A variant. These sequence mis-match effects were less pronounced when we used purified recombinant SOD1 that had been fibrilized in vitro as the seeding preparation. Collectively, our findings demonstrate diversity in the abilities of ALS variants of SOD1 to initiate or sustain prion-like propagation of misfolded conformations that produce motor neuron disease.

Supercharging Prions via Amyloid-Selective Lysine Acetylation.

Repulsive electrostatic forces between prion-like proteins are a barrier against aggregation. In neuropharmacology, however, a prion's net charge (Z) is not a targeted parameter. Compounds that selectively boost prion Z remain unreported. Here, we synthesized compounds that amplified the negative charge of misfolded superoxide dismutase-1 (SOD1) by acetylating lysine-NH3+ in amyloid-SOD1, without acetylating native-SOD1. Compounds resembled a "ball and chain" mace: a rigid amyloid-binding "handle" (benzothiazole, stilbene, or styrylpyridine); an aryl ester "ball"; and a triethylene glycol chain connecting ball to handle. At stoichiometric excess, compounds acetylated up to 9 of 11 lysine per misfolded subunit (ΔZfibril =-8100 per 103 subunits). Acetylated amyloid-SOD1 seeded aggregation more slowly than unacetylated amyloid-SOD1 in vitro and organotypic spinal cord (these effects were partially due to compound binding). Compounds exhibited reactivity with other amyloid and non-amyloid proteins (e.g., fibrillar α-synuclein was peracetylated; serum albumin was partially acetylated; carbonic anhydrase was largely unacetylated).

Il-10 signaling reduces survival in mouse models of synucleinopathy.

Parkinson's disease (PD) and related synucleinopathies are characterized by chronic neuroinflammation leading to the premise that anti-inflammatory therapies could ameliorate synucleinopathy and associated sequelae. To test this idea, we used recombinant adeno-associated viruses (AAV) to express the anti-inflammatory cytokine, Interleukin (Il)-10, in Line M83 transgenic mice that expresses the PD-associated A53T mutant human α-synuclein (αSyn). Contrary to our expectations, we observed that intraspinal Il-10 expression initiated at birth upregulated microgliosis and led to early death in homozygous M83+/+ mice. We further observed that Il-10 preconditioning led to reduced lifespan in the hemizygous M83+/- mice injected with preformed αSyn aggregates in hindlimb muscles. To determine the mechanistic basis for these adverse effects, we took advantage of the I87A variant Il-10 (vIl-10) that has predominantly immunosuppressive properties. Sustained intraspinal expression of vIl-10 in preformed αSyn-aggregate seeded M83+/- mice resulted in earlier death, accelerated αSyn pathology, pronounced microgliosis, and increased apoptosis compared to control mice. AAV-vIl-10 expression robustly induced p62 and neuronal LC3B accumulation in these mice, indicating that Il-10 signaling mediated preconditioning of the neuraxis can potentially exacerbate αSyn accumulation through autophagy dysfunction in the neurons. Together, our data demonstrate unexpected adverse effects of both Il-10 and its immunosuppressive variant, vIl-10, in a mouse model of PD, highlighting the pleiotropic functions of immune mediators and their complex role in non-cell autonomous signaling in neurodegenerative proteinopathies.

Reactive astrocytes as treatment targets in Alzheimer's disease-Systematic review of studies using the APPswePS1dE9 mouse model.

Astrocytes regulate synaptic communication and are essential for proper brain functioning. In Alzheimer's disease (AD) astrocytes become reactive, which is characterized by an increased expression of intermediate filament proteins and cellular hypertrophy. Reactive astrocytes are found in close association with amyloid-beta (Aß) deposits. Synaptic communication and neuronal network function could be directly modulated by reactive astrocytes, potentially contributing to cognitive decline in AD. In this review, we focus on reactive astrocytes as treatment targets in AD in the APPswePS1dE9 AD mouse model, a widely used model to study amyloidosis and gliosis. We first give an overview of the model; that is, how it was generated, which cells express the transgenes, and the effect of its genetic background on Aß pathology. Subsequently, to determine whether modifying reactive astrocytes in AD could influence pathogenesis and cognition, we review studies using this mouse model in which interventions were directly targeted at reactive astrocytes or had an indirect effect on reactive astrocytes. Overall, studies specifically targeting astrocytes to reduce astrogliosis showed beneficial effects on cognition, which indicates that targeting astrocytes should be included in developing novel therapies for AD.

Remodeling Alzheimer-amyloidosis models by seeding.

Alzheimer's disease (AD) is among the most prevalent neurodegenerative diseases, with brain pathology defined by extracellular amyloid beta deposits and intracellular tau aggregates. To aid in research efforts to improve understanding of this disease, transgenic murine models have been developed that replicate aspects of AD pathology. Familial AD is associated with mutations in the amyloid precursor protein and in the presenilins (associated with amyloidosis); transgenic amyloid models feature one or more of these mutant genes. Recent advances in seeding methods provide a means to alter the morphology of resultant amyloid deposits and the age that pathology develops. In this review, we discuss the variety of factors that influence the seeding of amyloid beta pathology, including the source of seed, the time interval after seeding, the nature of the transgenic host, and the preparation of the seeding inoculum.