Papers by Thomas Wisniewski
bioRxiv (Cold Spring Harbor Laboratory), Apr 14, 2023
Proteomic studies of human Alzheimer's disease brain tissue have exceptional potential to identif... more Proteomic studies of human Alzheimer's disease brain tissue have exceptional potential to identify protein changes that drive disease and to identify new drug targets. Here, we detail a combined analysis of 38 published Alzheimer's disease proteomic studies, generating a comprehensive map of protein changes in human brain tissue across thirteen brain regions, three disease stages (preclinical Alzheimer's disease, mild cognitive impairment, advanced Alzheimer's disease), and proteins enriched in amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. Our dataset is compiled into a user-friendly, searchable database called NeuroPro. Our combined analysis included 18,119 reported protein differences in human Alzheimer's disease brain tissue, which mapped to 5,311 total altered proteins. Proteomic studies were remarkably consistent. 848 proteins were consistently altered in ³5 studies, many of which are understudied in the Alzheimer's field. Comparison of protein changes in early-stage and advanced Alzheimer's disease revealed significant synapse, vesicle, and lysosomal changes early in disease, but widespread mitochondrial changes only in advanced Alzheimer's disease. Comparison of vulnerable and resistant brain regions suggested that protein changes in resistant regions in advanced Alzheimer's disease are similar to those in vulnerable regions in early-stage Alzheimer's disease, indicating a temporal progression of protein dysfunction during Alzheimer's disease advancement. We conclude that NeuroPro is a powerful new resource that provides new insights into human Alzheimer's disease brain protein changes and highlights novel proteins of particular interest that may mechanistically drive Alzheimer's disease.
Journal of Alzheimer's Disease, Nov 12, 2009
Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders... more Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. Prior to the side effects in the first Elan/ Wyeth AD vaccine trial, we proposed using amyloid-β (Aβ) derivatives as a safer approach. The route of administration may also affect vaccine safety. To assess the feasibility of oral immunization that promotes mucosal immunity, Tg2576 AD model mice were treated prophylactically three times over 6 weeks starting at 3−5 months of age with a Salmonella vaccine expressing K6Aβ1−30. At 22 −24 months of age, cortical Aβ plaque burden and total Aβ40/42 levels were reduced by 48−75% in the immunized mice compared to controls, which received unmodified Salmonella. Plaque clearance was not associated with increased microglial activation which may be explained by the long treatment period. Furthermore, cerebral microhemorrhages were not increased in the treated mice in contrast to several passive Aβ antibody studies. These results further support our findings with this immunogen delivered subcutaneously, and demonstrate its efficacy when given orally which may provide added benefits for human use.
Revue scientifique et technique, 2007
Prion diseases are a unique category of illness, affecting both animals and humans, where the und... more Prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformation change of the cellular form of a normal, self-protein called a prion protein (PrP(c) [C for cellular]) to a pathological and infectious conformation known as scrapie form (PrPsc [Sc for scrapie]). Currently, all prion diseases are without effective treatment and are universally fatal. The emergence of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease has highlighted the need to develop possible therapies. In Alzheimer's disease (AD), which has similarities to prion diseases, both passive and active immunisation have been shown to be highly effective at preventing disease and cognitive deficits in model animals. In a human trial of active vaccination in AD, despite indications of cognitive benefits in patients with an adequate humoral response, 6% of patients developed significant complications related to excessive...
Journal of Alzheimer's Disease, 2001
An important event in the pathogenesis of Alzheimer's disease (AD) is the deposition of the amylo... more An important event in the pathogenesis of Alzheimer's disease (AD) is the deposition of the amyloid β (Aβ)1-40 and 1-42 peptides in a fibrillar form, with Aβ42 typically having a greater propensity to undergo this conformational change. A major risk factor for late-onset AD is the inheritance of the apolipoprotein E (apoE) 4 allele [3,14,31]. We previously proposed that apoE may function as a "pathological chaperone" in the pathogenesis of AD (i.e. modulate the structure of Aβ, promoting or stabilizing a β-sheet conformation), prior to the discovery of this linkage [7,40-42]. Data from apoE knockout / AβPP V717F mice, has shown that the presence of apoE is necessary for cerebral amyloid formation [1, 2], consistent with our hypothesis. However, in AβPP V717F mice expressing human apoE3 or E4 early Aβ deposition at 9 months is suppressed, but by 15 months both human apoE expressing mice had significant fibrillar Aβ deposits with the apoE4 expressing mice having a 10 fold greater amyloid burden [8,9]. This and other data has suggested that apoE, in addition to having a facilitating role in fibril formation, may also influence clearance of Aβ peptides. In order to address if apoE affects the clearance of Aβ peptides across the bloodbrain barrier (BBB) and whether there are differences in the clearance of Aβ40 versus Aβ42, we performed stereotactic, intra-ventricular micro-injections of Aβ40, Aβ42 or control peptides in wild-type, apoE knockout (KO) or human apoE3 or apoE4 expressing transgenic mice. We found that consistent with other studies [5], Aβ40 is rapidly cleared from the brain across the BBB; however, Aβ42 is cleared much less effectively. This clearance of exogenous Aβ peptides across the BBB does not appear to be affected by apoE expression. This data suggests that Aβ42 production may favor amyloid deposition due to a reduced clearance across the BBB, compared to Aβ40. In addition, our experiments support a role of apoE as a pathological chaperone, and do not suggest an isotype specific role of apoE in exogenous Aβ peptide clearance from the CSF across the BBB.
Journal of Neuropathology & Experimental Neurology, 2000
Cerebral amyloid- (A) deposition is central to the neuropathological definition of Alzheimer di... more Cerebral amyloid- (A) deposition is central to the neuropathological definition of Alzheimer disease (AD) with A related toxicity being linked to its -sheet conformation and/or aggregation. We show that a -sheet breaker peptide (iA5) dose-dependently and reproducibly induced in vivo disassembly of fibrillar amyloid deposits, with control peptides having no effect. The iA5-induced disassembly prevented and/or reversed neuronal shrinkage caused by A and reduced the extent of interleukin-1 positive microglia-like cells that surround the A deposits. These findings suggest that -sheet breakers, such as iA5 or similar peptidomimetic compounds, may be useful for reducing the size and/or number of cerebral amyloid plaques in AD, and subsequently diminishing A-related histopathology.
Journal of the American Chemical Society, Jan 7, 2015
Aggregation of amyloid β-peptide (Aβ) is implicated in the pathology of Alzheimer's disease (... more Aggregation of amyloid β-peptide (Aβ) is implicated in the pathology of Alzheimer's disease (AD), with the soluble, Aβ oligomeric species thought to be the critical pathological species. Identification and characterization of intermediate species formed during the aggregation process is crucial to the understanding of the mechanisms by which oligomeric species mediate neuronal toxicity and following disease progression. Probing these species proved to be extremely challenging, as evident by the lack of reliable sensors, due to their heterogeneous and transient nature. We describe here an oligomer-specific fluorescent chemical probe, BoDipy-Oligomer (BD-Oligo), developed through the use of the diversity-oriented fluorescent library approach (DOFLA) and high-content, imaging-based screening. This probe enables dynamic oligomer monitoring during fibrillogenesis in vitro and shows in vivo Aβ oligomers staining possibility in the AD mice model.
The Journal of Neuroscience, 2004
Immunization with amyloid-β (Aβ) 1-42 has been shown to reduce amyloid burden and improve cogniti... more Immunization with amyloid-β (Aβ) 1-42 has been shown to reduce amyloid burden and improve cognition in Alzheimer's disease (AD) model mice. In a human trial, possible cognitive benefit was found but in association with significant toxicity in a minority of patients. We proposed that immunization with nonfibrillogenic Aβ derivatives is much less likely to produce toxicity and have previously shown that one such derivative (K6Aβ1-30) can reduce amyloid burden in mice to a similar extent as Aβ1-42. Here, we immunized AD model mice (Tg2576) with Aβ1-30[E18E19] or with K6Aβ1-30[E18E19]. These peptides were designed to be nontoxic and to produce less T-cell response, which has been linked to toxicity. K6Aβ1-30[E18E19] induced primarily an IgM response, whereas Aβ1-30[E18E19] induced an IgG titer that was lower than previously seen with K6Aβ1-30 or Aβ1-42. However, both treated animal groups performed better than Tg controls in the radial arm maze. Amyloid burden was similar in Aβ1-30[...
The Journal of Neuroscience, 2009
The pathogenesis of Alzheimer's disease (AD) is thought to be related to the accumulation of ... more The pathogenesis of Alzheimer's disease (AD) is thought to be related to the accumulation of amyloid β (Aβ) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Aβ accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p= 0.0001) and vascular (p= 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Aβ42, Aβ40, and Aβ oligomer levels. We also show that treated Tg mice performed similarl...
Neurobiology of Aging, 2008
Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contr... more Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contrast agent is presented, Gd-DTPA-K6A1-30, which is homologous to A, and allows plaque detection in vivo. MRI was performed on AD model mice and controls prior to and following intracarotid injection with Gd-DTPA-K6A1-30 in mannitol solution, to transiently open the blood-brain barrier. A gradient echo T2 *-weighted sequence was used to provide 100 m isotropic resolution with imaging times of 115 min. The scans were examined with voxel-based analysis (VBA) using statistical parametric mapping, for un-biased quantitative comparison of ligand-injected mice and controls. The results indicate that: (1) Gd-DTPA-K6A1-30 is an effective, non-toxic, ligand for plaque detection when combined with VBA (p ≤ 0.01-0.001), comparing pre and post-ligand injection scans. (2) Large plaques can be detected without the use of a contrast agent and this detection co-localizes with iron deposition. (3) Smaller, earlier plaques require contrast ligand for MRI visualization. Our ligand when combined with VBA may be useful for following therapeutic approaches targeting amyloid in transgenic mouse models.
Journal of Virology, 2008
ABSTRACTPrion diseases such as scrapie involve the accumulation of disease-specific prion protein... more ABSTRACTPrion diseases such as scrapie involve the accumulation of disease-specific prion protein, PrPSc, in the brain. Toll-like receptors (TLRs) are a family of proteins that recognize microbial constituents and are central players in host innate immune responses. The TLR9 agonist unmethylated CpG DNA was shown to prolong the scrapie incubation period in mice, suggesting that innate immune activation interferes with prion disease progression. Thus, it was predicted that ablation of TLR signaling would result in accelerated pathogenesis. C3H/HeJ (Tlr4Lps-d) mice, which possess a mutation in the TLR4 intracellular domain preventing TLR4 signaling, and strain-matched wild-type control (C3H/HeOuJ) mice were infected intracerebrally or intraperitoneally with various doses of scrapie inoculum. Incubation periods were significantly shortened in C3H/HeJ compared with C3H/HeOuJ mice, regardless of the route of infection or dose administered. At the clinical phase of disease, brain PrPSclev...
Journal of Leukocyte Biology, 2007
Prion diseases are characterized by conversion of the cellular prion protein (PrPC) to a protease... more Prion diseases are characterized by conversion of the cellular prion protein (PrPC) to a protease-resistant conformer, the srapie form of PrP (PrPSc). Humoral immune responses to nondenatured forms of PrPSc have never been fully characterized. We investigated whether production of antibodies to PrPSc could occur in PrP null (Prnp−/−) mice and further, whether innate immune stimulation with the TLR9 agonist CpG oligodeoxynucleotide (ODN) 1826 could enhance this process. Whether such stimulation could raise anti-PrPSc antibody levels in wild-type (Prnp+/+) mice was also investigated. Prnp−/− and Prnp+/+ mice were immunized with nondenatured 139A scrapie-associated fibrils (SAF), with or without ODN 1826, and were tested for titers of PrP-specific antibodies. In Prnp−/− mice, inclusion of ODN 1826 in the immunization regime increased anti-PrP titers more than 13-fold after two immunizations and induced, among others, antibodies to an N-terminal epitope, which were only present in the i...
Expert Review of Vaccines, 2005
Promising developments in prion immunotherapy '...the potential of numerous asymptomatic carriers... more Promising developments in prion immunotherapy '...the potential of numerous asymptomatic carriers raises a major threat to blood banks and organ transplant recipients.'
Biochemical Society Transactions, 2002
There is increasing recognition that numerous neurodegenerative conditions have the same underlyi... more There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the β-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-β peptide (sAβ) to Aβ plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrPc, to the disease-associated form, PrPsc. This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the confor...
American Journal of Psychiatry, 2012
Objective-Major depressive disorder is common in the elderly, and symptoms are often not responsi... more Objective-Major depressive disorder is common in the elderly, and symptoms are often not responsive to conventional antidepressant treatment, especially in the long term. Soluble oligomeric and aggregated forms of amyloid beta peptides, especially amyloid beta 42, impair neuronal and synaptic function. Amyloid beta 42 is the main component of plaques and is implicated in Alzheimer's disease. Amyloid beta peptides also induce a depressive state in rodents and disrupt major neurotransmitter systems linked to depression. The authors assessed whether major depression was associated with CSF levels of amyloid beta, tau protein, and F2-isoprostanes in elderly individuals with major depressive disorder and age-matched nondepressed comparison subjects. Method-CSF was obtained from 47 cognitively intact volunteers (major depression group, N=28; comparison group, N=19) and analyzed for levels of soluble amyloid beta, total and phosphorylated tau proteins, and isoprostanes. Results-Amyloid beta 42 levels were significantly lower in the major depression group relative to the comparison group, and amyloid beta 40 levels were lower but only approaching statistical significance. In contrast, isoprostane levels were higher in the major depression group. No differences were observed in total and phosphorylated tau proteins across conditions. Antidepressant use was not associated with differences in amyloid beta 42 levels. Conclusions-Reduction in CSF levels of amyloid beta 42 may be related to increased brain amyloid beta plaques or decreased soluble amyloid beta production in elderly individuals with major depression relative to nondepressed comparison subjects. These results may have implications for our understanding of the patho-physiology of major depression and for the development of treatment strategies. An association between Alzheimer's disease and major depressive disorder has been reported in some studies, suggesting that depression could be considered either a risk factor
The American Journal of Pathology, 2001
Transgenic mice with brain amyloid- (A) plaques immunized with aggregated A1-42 have reduced c... more Transgenic mice with brain amyloid- (A) plaques immunized with aggregated A1-42 have reduced cerebral amyloid burden. However, the use of A1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic A homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P ؍ 0.0002) and 81% (P ؍ 0.0001), respectively. Concurrently, brain levels of soluble A1-42 were reduced by 57% (P ؍ 0.0019). Ramified microglia expressing interleukin-1 associated with the A plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic A derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic A fibrils.
The American Journal of Pathology, 2002
The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially lar... more The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has been shown to be effective in mouse models of another neurodegenerative condition, namely Alzheimer's disease. Here we report that vaccination with recombinant mouse prion protein delays the onset of prion disease in mice. Vaccination was performed both before peripheral prion exposure and after exposure. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized before exposure. The increase in the incubation period closely correlated with the antiprion protein antibody titer. This promising finding suggests that a similar approach may work in humans or other mammalian species at risk for prion disease.
The American Journal of Pathology, 2004
Acta Neuropathologica, 2007
Amyloid (A) immunoreactivity in neurons was examined in brains of 32 control subjects, 31 people ... more Amyloid (A) immunoreactivity in neurons was examined in brains of 32 control subjects, 31 people with Down syndrome, and 36 patients with sporadic Alzheimer's disease to determine if intraneuronal A immunoreactivity is an early manifestation of Alzheimer-type pathology leading to Wbrillar plaque formation and/or neuroWbrillary degeneration. The appearance of A immunoreactivity in neurons in infants and stable neuron-type speciWc A immunoreactivity in a majority of brain structures during late childhood, adulthood, and normal aging does not support this hypothesis. The absence or detection of
Annals of neurology, Jan 2, 2018
Multiple system atrophy (MSA) is a fatal neurodegenerative disorder that causes autonomic failure... more Multiple system atrophy (MSA) is a fatal neurodegenerative disorder that causes autonomic failure, parkinsonism, and cerebellar ataxia in any combination. 1 Pathological hallmarks of this condition are α-synuclein rich glial cytoplasmatic inclusions (GCIs). 2,3 Misfolded αsynuclein aggregates can be identified also in Parkinson's disease (PD) and Lewy body (LB) dementia (DLB), therefore defining a family of diseases called α-synucleinopathies. In contrast to PD and DLB, in MSA aggregated or pathological α-synuclein selectively accumulates within glial cells and rarely within neurons. 4,5 The etiology and the pathogenic mechanism leading to α-synuclein misfolding and deposition remain unclear. 6,7 Prusiner et al., recently published a series of papers 8-11 in which they assessed whether αsynuclein aggregates may act as prions and whether MSA is a prion disease. In Prusiner's definition, prion is a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids. 12 Infectivity is broadly accepted as a core feature of prions, and is therefore required to define prion diseases. For this reason, Prusiner's hypothesis has several theoretical and practical implications.
Acta neuropathologica, Jan 17, 2015
The relationship between primary age-related tauopathy (PART) and Alzheimer's disease (AD) is cur... more The relationship between primary age-related tauopathy (PART) and Alzheimer's disease (AD) is currently a matter of discussion. Recently the term PART was referred to cases characterized by mainly allocortical neurofibrillary (NF) pathology (Braak stages 0-IV) with only few or no amyloid (Aβ) deposits (Thal Aβ phases 0-2) [49]. In addition, no elevated soluble Aβ was detected in this disorder [9, 46]. PART cases that lack any Aβ do not meet formal criteria for sporadic AD according to the NIA-AA guidelines [35]. These neurofibrillary tangle (NFT)+/Aβ-brains are commonly observed in extreme old age [9, 15, 19]. When associated with a high density of NFTs in the same distribution and some cognitive deficits, the disorder has been referred to as tangle-predominant senile dementia (TPSD) [27] or "tangle-only dementia" [55].
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Papers by Thomas Wisniewski