prion-like protein aggregates and type 2...

Prion-Like Protein Aggregatesand Type 2 Diabetes

Abhisek Mukherjee and Claudio Soto

Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology,University of Texas Health Science Center, McGovern Medical School, Houston, Texas 77030

Correspondence: [email protected]

Type 2 diabetes (T2D) is a highly prevalent metabolic disease characterized by chronicinsulin resistance and b-cell dysfunction and loss, leading to impaired insulin release andhyperglycemia. Although the mechanism responsible for b-cell dysfunction and death is notcompletely understood, recent findings suggest that the accumulation of misfolded aggre-gates of the islet amyloid polypeptide (IAPP) in the islets of Langerhans may playan importantrole in pancreatic damage. Misfolding and aggregation of diverse proteins and theiraccumulation as amyloid in different organs is the hallmark feature in a group of chronic,degenerative diseases termed protein misfolding disorders (PMDs). PMDs include highlyprevalent human illnesses such as Alzheimer’s and Parkinson’s disease, as well as morethan 25 rarer disorders. Among them, prion diseases are unique because the pathologycan be transmitted by a proteinaceous infectious agent, termed a prion, which inducesdisease by propagating protein misfolding and aggregation. This phenomenon has a strikingresemblance to the process of protein misfolding and aggregation in all of the PMDs, sug-gesting that misfolded aggregates have an intrinsic potential to be transmissible. Indeed,recent studies have shown that the pathological hallmarks of various PMDs can beinduced in vivo under experimental conditions by inoculating tissue extracts containingprotein aggregates into animal models. In this review, we describe our current understandingof the molecular mechanism underlying the prion-like transmission of protein aggregatesand its possible role in T2D.

Protein misfolding disorders (PMDs) are agroup of diseases in which at least one pro-

tein or peptide has been shown to misfold, ag-gregate, and accumulate in tissues, leading tocellular damage and organ dysfunction. Thereare at least 25 different diseases in the PMDgroup, including several neurodegenerative dis-orders such as Alzheimer’s disease (AD), Par-kinson’s disease (PD), Huntington’s disease(HD), the transmissible spongiform encepha-

lopathies (TSEs), and amyotrophic lateral scle-rosis (ALS), as well as diverse systemic disorderssuch as familial amyloid polyneuropathy, type 2diabetes (T2D), secondary amyloidosis, and di-alysis-related amyloidosis (Soto 2003). Earlypostmortem histopathological studies linkedthe accumulation of protein deposits composedof different proteins (such as Ab and tau in AD,a-synuclein in PD, polyglutamine [polyQ] ex-tended huntingtin in HD, islet amyloid poly-

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peptide [IAPP] in T2D, and prion protein [PrP]in TSEs) with disease pathology (Soto 2003).Genetic studies have shown that mutations inthe genes encoding the proteins that predomi-nantly compose the aggregates are associatedwith inherited transmission of many PMDs(Hardy and Gwinn-Hardy 1998; Soto 2003).Vertical transmission of these mutations result-ed in an extensive burden of protein aggregates,earlier disease onset, and increased disease se-verity compared with sporadic cases (Hardy andGwinn-Hardy 1998). Finally, transgenic expres-sion of disease-specific human genes harboringthe associated mutations in animal models re-produced several clinical and pathological char-acteristics of PMDs, supporting the key contri-bution of protein aggregates in these diseases(Moreno-Gonzalez and Soto 2012). AmongPMDs, prion diseases are considered uniquebecause misfolded prions transmit diseasethrough an infectious route (Prusiner 1998).Aggregates of misfolded prion protein transmitdisease by seeding the aggregation of the hostprion protein, resulting in the accumulation oflarge quantities of these toxic aggregates in thebrain (Prusiner 1998; Soto et al. 2006; Soto2012). Interestingly, we and others have recentlydemonstrated that several amyloid pathologiescan be experimentally transmitted by a prion-like mechanism in various cellular and animalmodels of diverse diseases (Desplats et al. 2009;Frost et al. 2009; Ren et al. 2009; Brundin et al.2010; Westermark and Westermark 2010; Juckerand Walker 2011; Prusiner 2012; Soto 2012).Furthermore, the prion-like propagation of ag-gregates appears to significantly contribute tothe spatiotemporal spreading of disease pathol-ogy in affected individuals. In this review, wediscuss the role of protein misfolding in T2Dand the possibility of prion-like transmissionof T2D-associated protein aggregates.

TYPE 2 DIABETES AND IAPP AGGREGATES

T2D, also known as non-insulin-dependent di-abetes (NIDDM), is awidespread metabolic dis-ease. It is most prevalent in adults over the age of40 and accounts for 90%–95% of the total num-ber of diabetic patients. Currently, 285 million

people worldwide are affected by T2D, and thenumber is predicted to increase progressively infuture years, reaching as many as 438 million by2030 (Shamseddeen et al. 2011). Clinicopatho-logically, T2D is characterized by chronic insulinresistance, progressive loss of b-cell function(Kahn 2003), and b-cell mass (Butler et al.2003), leading to impaired insulin release andhyperglycemia. In healthy individuals, insulin,which is secreted by b-cells in pancreatic islets,plays a major role in maintaining a normalblood sugar level (euglycemia). During insulinresistance, when normal levels of insulin fail tomaintain euglycemia, there is a compensatoryincrease in insulin secretion from b-cells. How-ever, genetic and environmental factors are be-lieved to predispose some individuals (�20% ofthe population) to b-cell failure under chronicinsulin resistance (Kahn et al. 2014). Both dys-function and loss of b-cells are frequently as-cribed to be consequences of glucolipotoxicity(Poitout and Robertson 2002; El-Assaad et al.2003), islet cholesterol accumulation (Brunhamet al. 2010), and islet inflammation (Donath andShoelson 2011). However, accumulating evi-dence suggests that toxic aggregates of IAPP, aneuroendocrine polypeptide hormone (Wester-mark et al. 1987), or amylin (Cooper et al. 1988)may substantially contribute to b-cell dysfunc-tion and loss (Hull et al. 2004; Haataja et al.2008).

IAPP is predominantly expressed by b-cellsas 89-amino-acid pre-pro-IAPP. After process-ing in the endoplasmic reticulum (ER)–Golginetwork (Wang et al. 2001; Marzban et al. 2004,2005), the 37-amino-acid-long IAPP is storedin secretory granules with insulin, awaitingstimulus for secretion. Although the exact roleof IAPP in diabetes is not fully understood, itsproposed functions include inhibition of insu-lin secretion, delay in gastric emptying, dimin-ishing appetite, suppression of glucagon release(for review, see Westermark et al. 2011), andsuppression of tumorigenesis (Venkatanarayanet al. 2015).

IAPP amyloid accumulation was initiallyobserved more than 100 years ago (Opie 1901).However, the clinical significance of this obser-vation remained unappreciated because not all

A. Mukherjee and C. Soto

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of the T2D patients manifested islet amyloid.Also, low levels of islet amyloid were found inhealthy individuals (Ludwig and Heitner 1967;Westermark 1972; Westermark and Wilander1978). Further studies established that islet am-yloid deposits can be found in .90% of T2Dpatients (Westermark 1972; Clark et al. 1988;Betsholtz et al. 1989b; Johnson et al. 1989; Jur-gens et al. 2011). Eventually, studies of otherPMDs (such as AD or PD) showed that aged,healthy individuals, presumably in the processof developing the disease, may show a substan-tial accumulation of protein aggregates (Pikeet al. 2007; Chetelat et al. 2013). Several studieslinked IAPP aggregation with b-cell loss and theprogression of T2D. Pancreatic b-cell mass isdetermined by a balance between individualb-cell size, proliferation, neogenesis, and apo-ptosis. Autopsy studies from T2D patients sug-gested that IAPP aggregates are associated withincreasing b-cell apoptosis, leading to loss of b-cell mass (Clark et al. 1988; Butler et al. 2003;Jurgens et al. 2011). Similarly, IAPP aggregationwas suggested to be a crucial determinant of de-clining b-cell function in clinically transplantedislets (Westermark et al. 2005). Mutation in theIAPP gene, which enhances its amyloid formingpropensity (Sakagashira et al. 2000; Ma et al.2001), was associated with early induction ofT2D (Lee et al. 2001; Seino 2001). Longitudinalstudies in animals that spontaneously developT2D (nonhuman primates and domestic cats)and mimic the clinicopathological progressionof the disease in humans revealed that islet am-yloid severity (percentage of islet area occupiedby aggregates) strongly correlates with diseasepathology. Furthermore, formation of IAPP ag-gregates precedesb-cell dysfunction and clinicalsigns of the disease in these animals (Howard1986; de Koning et al. 1993; Ma et al. 1998;Guardado-Mendoza et al. 2009).

The IAPP sequence is generally conserved;however, there are a few critical interspecies dif-ferences in the most amyloidogenic region (res-idues 20–29) (Westermark et al. 1990). Inter-estingly, species that are known to express anamyloid-prone sequence of IAPP, including hu-mans, monkeys, and domestic cats, are also thespecies known to spontaneously develop T2D

(Cefalu 2006). Islet amyloid has been found in alarge proportion of diabetic cats and cynomol-gus macaques (Howard 1986; de Koning et al.1993; Ma et al. 1998; Henson and O’Brien2006). The presence of three proline residues(a well-known b-sheet-breaking amino acid)(Soto and Estrada 2005) within the 20–29 amy-loidogenic region in rodent IAPP, compared tohuman, substantially reduces the propensity ofIAPP to misfold and aggregate (Betsholtz et al.1989a; Soto and Estrada 2005). SpontaneousT2D is not reported in untreated rodents, andthe rodent models that are often used to reca-pitulate T2D (such as high-fat-diet-induced di-abetic mice or ob/ob mice) do not produce isletamyloid (Chatzigeorgiou et al. 2009). However,overexpression of the human IAPP sequence inrodents resulted in the accumulation of IAPPaggregates in islets, leading to clinical and path-ological hallmarks of T2D (Janson et al. 1996;Matveyenko and Butler 2006). In a recent re-view, we summarized the mechanism of IAPPaggregate formation and toxicity and estab-lished a detailed comparison with other proteinaggregates associated with PMDs of the centralnervous system (CNS), such as amyloid-b (Ab)and tau in AD, a-synuclein in PD, or prions inprion diseases (Mukherjee et al. 2015). Here, wewill focus on the possibility of prion-like prop-agation of IAPP aggregates and their putativerole in T2D.

MISFOLDED PROTEIN AGGREGATES ASINFECTIOUS AGENTS: THE PRION STORY

Prion diseases are a group of fatal neurodegen-erative diseases that affect humans, cattle, andseveral other mammals (Soto 2011). The hall-mark event in prion disease is the conversion ofthe native prion protein (PrPC) into a mis-folded, aggregated, and protease-resistant con-formation called PrPSc, followed by its accumu-lation in the brain (Prusiner 1998). Clinically,prion diseases are characterized by a long pre-symptomatic phase in which PrPSc accumulatessilently and progressively. This phase is followedby an aggressive and usually short symptomaticphase that leads inevitably to death (Prusiner1998). Prion diseases can be transmitted from

Prion-Like Protein Aggregates and Type 2 Diabetes

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animal to animal, animal to human, or humanto human by an unorthodox infectious agent(devoid of nucleic acids) thought to be solelycomposed of the misfolded prion protein (Pru-siner 1998). At the molecular level, the mecha-nism of prion transmission is best explained bythe seeding/nucleation model of protein aggre-gation. This model is characterized by an initiallag phase in which the protein misfolds and self-associates, forming small oligomers that act asnuclei or seeds to catalyze further polymeriza-tion. Once the seed is formed, it can nucleate/seed aggregation of large amounts of mono-mers, forming aggregates comprising a dynamicrange of sizes. Large aggregates can be fragment-ed to produce more seeds, leading to a viciouscycle (Jarrett and Lansbury 1993; Soto et al.2006). Prion infectivity depends on the abilityof misfolded prion protein aggregates to nucle-ate the misfolding and aggregation of the hostprion protein (Soto 2012). In cases of priondisease in both mammals and humans, it hasbeen shown that infection can be initiated byexposure to PrPSc-contaminated materials(i.e., tissue, blood, and surgical materials). Theacquisition of these exogenous seeds transmitsthe disease by inducing the conversion of theendogenous prion protein, resulting in a largeaccumulation of toxic PrPSc in the brain (Pru-siner 1998; Soto 2012).

SPREADING OF PROTEIN AGGREGATESWITHIN AFFECTED TISSUE AND ITSPOSSIBLE ROLE IN T2D PATHOLOGY

Interestingly, the formation of misfolded aggre-gates in all other PMDs follows the same seed-ing/nucleation principle responsible for prionreplication (Soto 2012), suggesting that otherPMDs may also be transmissible in a similarmanner as prions (Soto et al. 2006; Soto2012). The possibility that other protein aggre-gates may be transmissible has been supportedby a large collection of recent studies demon-strating prion-like propagation of protein ag-gregates associated with AD, PD, HD, and ALS(Danzer et al. 2009; Frost et al. 2009; Ren et al.2009). In fact, cell-to-cell propagation of pro-tein aggregates has been suggested to play a key

role in the spatiotemporal progression of thepathology within the affected tissues (Guo andLee 2014). Propagation of the protein aggregatesfrom cell to cell appears to depend on theextracellular release of the aggregates and theirinternalization by their neighboring cells. Deathof aggregate-laden cells or shuttling exosomeshas been shown to contribute to the release ofaggregates to the extracellular space (Fevrieret al. 2004; Rajendran et al. 2006; Aguzzi andRajendran 2009). Endocytosis, pinocytosis, orsimple diffusion through membranes betweenadjacent cells has been proposed as the mecha-nism of cellular internalization of these aggre-gates in various PMDs (Burdick et al. 1997;Sung et al. 2001; Nagele et al. 2002; Frost et al.2009). It is also possible that aggregates aretransferred directly from cell to cell withoutthe need to move through the extracellularspace, for example, by transsynaptic connec-tions or tunneling nanotubes (Liu et al. 2012;Costanzo et al. 2013).

In the case of IAPP, evidence shows thatIAPP oligomerization begins intracellularly,perhaps in secretory granules of islet b-cells(Gurlo et al. 2010). Degenerating b-cells mayrelease these aggregates, which subsequently ac-cumulate extracellularly as large amyloid depos-its, a process that occurs in several other system-ic amyloid diseases. Indeed, it has been reportedthat the number of b-cells is selectively de-creased in islets containing IAPP aggregates(Jurgens et al. 2011). It is interesting to notethat our own studies have shown that large am-yloid fibrils are able to release oligomers capableof forming seeds under physiological condi-tions (Shahnawaz and Soto 2012). Based onthe findings obtained in other PMDs, it seemspossible that IAPP aggregates may be able topropagate from b-cell to b-cell and perhapseven from islet to islet. The proximity amongb-cells and the fact that IAPP aggregates appearto be released from cells to the extracellularspace supports cell-to-cell transmission. A cru-cial question is whether IAPP aggregates canpropagate from one islet to another by a pri-on-like mechanism. Although there is no directevidence, studies of pancreatic tissue from T2Dpatients have shown that amyloid formation



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initiates in one or a few islets; then at least insome cases, it gradually spreads to other islets inthe pancreas (Westermark 1972; Westermarket al. 2011). Similar results were obtained froma longitudinal study in baboons in which isletamyloids were found, initially in 0%–50% ofislets without significant change in the total am-yloid load. In the second stage, both amyloidseverity and prevalence (percentage of islet con-taining amyloid) increased (9.5%–47.3% and50%–95%, respectively), followed by a signi-

ficant increase in amyloid severity (47.3%–68.9%) in the third stage (Guardado-Mendozaet al. 2009). It is important to consider that isletsin the pancreas are not physically connected.Therefore, spreading of IAPP aggregates withinthe pancreas requires a specific route (Fig. 1).The most obvious candidate is by blood circu-lation because islets are highly vascularized.IAPP aggregates were found between b-cellsand adjacent capillaries in both human and ro-dent models of T2D (de Koning et al. 1994). It is

Large extra-cellular IAPPaggregates

β-cell

Arterial blood flow

Venous blood flow

Axon innervation

Brain

IAPP aggregate-containing islet, shown withvasculature and innervation

IAPP aggregate-free islet, shown withvasculature and innervation

Small, intra-cellular IAPPaggregates

Heart

Kidney

Pancreas

β

β

Figure 1. A schematic model of the possible mechanisms of islet amyloid polypeptide (IAPP) aggregate prop-agation from islet to islet and spreading into other tissues. IAPP aggregates in individuals with type 2 diabetes(T2D) are mostly located in the pancreas but have also been reported in other organs, including the kidney,heart, and brain. The figure shows how aggregates might spread through the circulation or peripheral nervoussystem. In the insets, two islets are shown with the vasculature and innervation. The top panel displays massiveamounts of IAPPaggregates, both in the form of small, intracellular species as well as large, extracellular deposits,located mostly between b-cells and adjacent capillaries. The axonal innervations from sympathetic, parasym-pathetic, and sensory nerves are shown in green. In the bottom panel, a similar islet is shown without IAPPaggregates. IAPP aggregates can hypothetically spread from islet to islet using both the circulation and theperipheral nervous system. The dotted black arrows indicate possible routes of IAPP aggregate spreading. For thesake of simplicity, only b-cells are shown in the islets. The diagram is not drawn to scale.



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important to highlight that the capillaries in theislets are highly fenestrated and permeable com-pared with those in the exocrine part of thepancreas (Henderson and Moss 1985). Howev-er, there is no direct evidence that IAPP aggre-gates can leak into the islet capillaries and spreadto other islets through circulation. Interestingly,a recent study demonstrated that intravenousinjection of synthetic IAPP aggregates can accel-erate IAPP aggregate formation in islets in arodent model of T2D (Oskarsson et al. 2015).Although the amount of IAPP injected in thisstudy is substantially higher than the physiolog-ical level of IAPP found in the blood, these re-sults strongly suggest that blood can be an effec-tive route for spreading of IAPP aggregates fromislet to islet. Furthermore, IAPP deposits posi-tively stained with Congo red were found inblood vessels of the brain from individuals af-fected by T2D, suggesting that IAPP aggregatesmight be present in the circulation (Jacksonet al. 2013). It is generally believed that isletsare highly innervated by parasympathetic, sym-pathetic, and sensory projections (Ahren 2000).Protein aggregates related to many PMDs of theCNS have been shown to be efficiently trans-ferred through transsynaptic connections,both anterogradely and retrogradely (for review,see Guo and Lee 2014). In fact, transsynapticspreading of protein aggregates was recentlyfound to play a key role in the spatiotemporalprogress of the disease lesions in models of AD,PD, ALS, and dementia with Lewy bodies.Whether IAPP aggregates are able to spreadfrom islet to islet via innervating axons andthe autonomic ganglia is unknown. It is alsoimportant to consider that the architecture ofthe islets, including b-cell arrangement by thecapillaries and the extent of innervation, can besignificantly different in different species (Boscoet al. 2010; Rodriguez-Diaz et al. 2011).

PRION-LIKE TRANSMISSION OF PROTEINAGGREGATES IN “REAL LIFE” AND ITSPOSSIBLE ROLE IN THE ETIOLOGY OF T2D

As discussed above, a series of recent studies hasshown that inoculation of tissue homogenatecontaining disease-specific protein aggregates

or aggregates made of pure proteins can induceor accelerate amyloid pathology in mouse mod-els by a prion-like mechanism of transmission.However, prions are currently the only proteinaggregates that have been convincingly demon-strated to be transmissible between individualsunder “real life” conditions. The potential forprotein aggregates to become infectious de-pends not only on their ability to convert hostprotein but also on the stability of the aggregatesin the biological system and the bioavailabilityin the tissue of interest (for a detailed discussionon this topic, see Soto 2012). Because the brainis heavily insulated from the rest of the body, itmay be difficult for protein aggregates acquiredalong systemic routes to reach the brain in suf-ficient quantities to initiate infection. Here lies aunique feature of prions, which exhibit an ex-tremely high resistance to cellular and physio-logical clearance mechanisms and are known toself-replicate in peripheral tissues, such as in thelymphatic organs (Aguzzi et al. 2013). It is likelythat prions acquired by peripheral routes aresubstantially amplified before reaching thebrain in large quantities. If this argument iscorrect, other PMDs of the CNS might not betransmissible in real life. This argument wouldalso suggest that systemic PMDs might have abetter chance to be transmissible under naturalconditions. Supporting this view, the only othercase of a PMD shown to be naturally transmis-sible between individuals is amyloid-A amy-loidosis in captive cheetahs (Zhang et al.2008). A similar transmission of amyloid-A am-yloidosis has also been suggested to cause anepidemic of avian amyloidosis (Murakamiet al. 2014). There are no epidemiological stud-ies that specifically consider whether T2D couldbe transmissible from individual to individual.Nevertheless, several studies suggest an infec-tious-like pandemic increase of T2D incidence.This is mostly attributed to changes in lifestyleand increase in obesity (Matthews and Mat-thews 2011). Interestingly, several reports indi-cate increased risk of diabetes after organ trans-plant (Kasiske et al. 2003; Carey et al. 2012) andblood transfusion (Chern et al. 2001). New-on-set diabetes after organ transplant (NODT),such as kidney transplant, is frequently ob-



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served in recipients (Kasiske et al. 2003; Careyet al. 2012). This is generally attributed to theuse of immunosuppressant drugs by the recip-ients. It is important to highlight that a recentstudy reported the presence of IAPP aggregatesin the kidney of 48.3% of patients with T2Dnephropathy (Gong et al. 2007). Individualswith diabetic nephropathy would likely not beconsidered as kidney donors; however, it is likelythat IAPP aggregates could begin to accumulatein the kidney before the appearance of any clin-ical symptoms of T2D. In fact, longitudinalstudies in nonhuman primates suggest thatIAPP accumulation in the pancreas begins wellbefore the appearance of any impairment inglucose metabolism (Guardado-Mendoza et al.2009). Moreover, a recent report indicates thatdiseased hearts from obese, prediabetic indi-viduals exhibit oligomeric IAPP, suggestingthat the process of IAPP accumulation maybegin decades before the onset of overt T2D(Despa et al. 2012). Increased risk of developingimpairment in glucose metabolism and diabe-tes has also been noted in individuals who havereceived chronic blood transfusion (Chern et al.2001; Shamshirsaz et al. 2003). Iron-overload-mediated toxicity in the endocrine system isbelieved to be the underlying cause. Conversely,a recent study reported the presence of oli-gomeric IAPP in the blood of diabetic rats (Sro-dulski et al. 2014). However, further studies arerequired to validate this claim. Although con-troversial, several studies have reported in-creased maternal inheritance of T2D in off-spring (Alcolado and Alcolado 1991; Younget al. 1995; Arfa et al. 2007). Gestational diabetesin mothers has also been shown to increase therisk of offspring developing diabetes (Damm2009). Furthermore, a study reported that theoffspring of women who were diabetic duringpregnancy were more likely to develop T2Dthan the offspring of women who developeddiabetes after giving birth (Pettitt et al. 1988).Mutations in the mitochondrial genome, genet-ic factors responsible for birth weight, and theintrauterine environment are believed to ex-plain the excess maternal inheritance of T2D(Lin et al. 1994; McCance et al. 1994; Moseset al. 1997). Insulin resistance, which is one of

the characteristics of gestational diabetes, maybe a prerequisite for pancreatic IAPP accumu-lation in a mouse model (Couce et al. 1996).Nevertheless, whether pancreatic IAPP aggre-gates are present in individuals suffering fromgestational diabetes is unknown. It is crucial tounderstand that all of this anecdotal evidencedoes not imply that T2D is transmissible. How-ever, it does warrant more specific epidemiolog-ical studies to fully investigate the possibility. Itis also important to highlight that epidemiolog-ical tracking of an infectious origin for diseasestransmitted by prion-like agents might be verydifficult considering the unorthodox rules oftransmission for protein-based agents (Soto2012), as well as the variable and extendedtime between exposure to the misfolded aggre-gates and the onset of clinical symptoms (Col-linge et al. 2006).

CROSS-SEEDING BETWEEN IAPP ANDOTHER PROTEIN AGGREGATESAND ITS ROLE IN T2D

Because the intermediate and end productsformed during the seeding/nucleation processare similar in all PMDs, seeds composed of oneprotein may catalyze the polymerization of oth-er proteins by a mechanism known as heterol-ogous seeding or cross-seeding (Morales et al.2013). The coexistence of multiple protein ag-gregates has been reported in various PMDs(Morales et al. 2013), and mixed pathologyseems to be the rule rather than the exception.The existence of one PMD has also been shownto increase the risk of developing other PMDs(Morales et al. 2013). Whether multiple proteinaggregates are present and contribute to T2Dpathology has not been studied in great detail.However, epidemiological studies have shownthat T2D patients exhibit an increased risk ofdeveloping AD compared with age-matchednondiabetic individuals (Biessels et al. 2006).IAPP deposition has been reported in the graymatter of the temporal lobe in the brains of T2Dpatients (Jackson et al. 2013). IAPP depositswere also found in both blood vessels andperivascular spaces, suggesting an influx fromperipheral circulation (Jackson et al. 2013).



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Interestingly, IAPP deposits in AD patient brainsco-localized with Ab amyloid plaques, suggest-ing a possible interaction between the two pro-teins. On the other hand, a large percentage ofAD patients simultaneously suffer from T2D orimpaired fasting glucose (Janson et al. 2004).Furthermore, AD patients show a higher inci-dence of islet amyloidosis than healthy individ-uals. The exact mechanism underlying the riskassociation between AD and T2D is not com-pletely understood. Several hypotheses havebeen proposed, including alterations in insulinsignaling, hypercholesterolemia, and oxidativestress. It is possible that misfolded proteins im-plicated in AD and T2D may interact with eachother, promoting their heterologous seedingand leading to an increased risk of the disease(Morales et al. 2013). In vitro studies report thatIAPP and Ab can cross-seed each other, enhanc-ing amyloid formation (Ono et al. 2014). Thepresence of Ab deposits and hyperphosphory-lated tau, the hallmark features of AD, is alsoreported in the islets of T2D patients, as is Abco-localized with IAPP aggregates (Miklossyet al. 2010). Furthermore, a recent study sug-gests that intravenous injection of pure Ab fi-brils can trigger islet amyloid formation in arodent model (Oskarsson et al. 2015). However,this group did not observe any Ab immunore-activity in the pancreas while analyzing a rela-tively small number (n ¼ 4) of T2D patients.The interaction may not be restricted to ADand T2D proteins. Indeed, the presence of olig-omeric a-synuclein was recently reported in is-lets of T2D patients and was suggested to impairglucose-stimulated insulin release from b-cells(Steneberg et al. 2013). Although there is somescattered evidence, the presence of other proteinaggregates in islets and their role in T2D has notyet been thoroughly explored.

FUTURE DIRECTIONS

Evidence showing that IAPP aggregates play akey role in T2D pathogenesis is compelling andis similar to evidence that has established proteinaggregates as the widely accepted cause of vari-ous neurodegenerative diseases. However, puta-tive relevance of IAPP aggregates in T2D is gen-

erally ignored by those in the diabetes researchfield, first because IAPPaggregates from islets aregenerally identified by histological methods, us-ing amyloid binding dyes such as thioflavin orCongo red. A thorough biochemical and bio-physical characterization, similar to that report-ed for the aggregates composed of Ab or prions,has yet to be performed. Islets constitute merely1%–2% of the pancreatic mass. Thus, the avail-ability of samples for objective characterizationis a limiting condition. Second, there are notsufficient studies to differentiate whether IAPPaggregates are inert bystanders that are the con-sequence of tissue damage during disease orwhether they play a crucial role in pathogenesis.Experiments that aim to induce islet amyloidpathology and at least some diabetes-like alter-ations, just by induction of IAPP aggregation,might be able to address this issue. Moreover,experiments that aim to inhibit islet pathologyby inhibiting IAPP aggregation will also providecrucial information. However, not many studieshave been done in this regard. From our exten-sive experience studying PMDs of the CNS andconsidering the current evidence that implicatesIAPP aggregates in T2D pathology (Mukherjeeet al. 2015), we argue that IAPP aggregates (per-haps smaller, soluble oligomers) may play a keyrole in contributing to T2D. The possibility thatIAPP aggregates might propagate from islet toislet or even from individual to individual cer-tainly presents a new area of research. b-cell pa-thology is closely associated with the presence ofIAPP aggregates in the same islets. Thus, prion-like propagation of IAPP aggregates might sig-nificantly contribute to the spread of islet lesionswithin the pancreas. Further research exploringthis possibility might lead to the discovery ofcrucial therapeutic targets that will inhibit thepropagation of IAPPaggregates fromb-cell tob-cell or from islet to islet, restricting the patho-logical progress of T2D.

ACKNOWLEDGMENTS

This work was supported in part by a grant fromthe National Institutes of Health (GM100453)to C.S. and a Jeane B. Kempner postdoctoralfellowship awarded to A.M.



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published online February 3, 2017Cold Spring Harb Perspect Med Abhisek Mukherjee and Claudio Soto Prion-Like Protein Aggregates and Type 2 Diabetes

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HomeostasisTherapeutic Strategies for Restoring Tau

GestwickiZapporah T. Young, Sue Ann Mok and Jason E.

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Katarzyna Lundmark, et al.Gunilla T. Westermark, Marcus Fändrich,

Neurodegenerative DiseaseFused in Sarcoma Neuropathology in

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ComplexesStructural and Chemical Biology of Presenilin

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DiseasesExperimental Models of Inherited PrP Prion

Joel C. Watts and Stanley B. Prusiner

http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

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