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The α-synuclein burden hypothesis of Parkinson disease and its relationship to Alzheimer disease
Experimental Neurology 212 (2008) 235–238
Contents lists available at ScienceDirect
Experimental Neurology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y e x n r
Commentary
The α-synuclein burden hypothesis of Parkinson disease and its relationship to Alzheimer disease Patrick L. McGeer ⁎, Edith G. McGeer Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C., Canada V6T 1Z3
A R T I C L E
I N F O
Article history: Received 31 January 2008 Revised 7 April 2008 Accepted 7 April 2008 Available online 20 April 2008
Over the past 8 decades, clinicians have observed that Parkinson disease (PD) patients frequently become demented as their disease progresses. The definition of diffuse Lewy body disease (DLB) as a contributing cause of dementia has opened up a new, and largely unsolved relationship between this more recently described entity, and the classical entities of Parkinson disease (PD) and Alzheimer disease (AD). The clinical as well as the pathological findings of these three entities overlap. Together, they are by far the most common neurodegenerative diseases associated with aging and vigorous research into their causation is a major health priority. They are inexorably progressive, slowly destroying selective areas of the brain in the absence of such conventional causes of neuronal death as infection, neoplasia, malnutrition and vascular insufficiency. In their early stages, they have quite different clinical and pathological manifestations. PD is characterized by deficits in movement with intact cognition, while AD is characterized by deficits in cognition with intact movement. DLB is in between, with cognitive and motor deficits being intertwined. The early cognitive deficits of DLB can be distinguished from those of AD since they frequently involve visual hallucinations and fluctuating attention rather than loss of short term memory. To distinguish DLB as a distinct entity, international meetings of experts have been held to draw up consensus clinical criteria for labeling cases as DLB or simply PD with dementia (McKeith et al., 2005; Emre et al., 2007). An arbitrary rule has emerged which is to define DLB as a disease where dementia appears within 1 year of the development of motor symptoms, whereas PD with dementia is where the onset of dementia takes longer than a year. Such a division is obviously artificial, and since no biochemical distinctions have been identified, it is hard to escape the conclusion that these are manifestations of a single disease entity.
⁎ Corresponding author. Fax: +1 604 822 7086. E-mail address: [email protected] (P.L. McGeer). 0014-4886/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2008.04.008
From an etiological point of view it might appropriately be referred to as the PD/DLB complex even though clinical distinctions will continue to be made. Such a general designation should help to focus efforts on developing new therapeutic agents that will deal with the underlying pathology. Pathologically, AD is characterized by plaques and tangles with high neuronal dropout in the paleocortex and selective areas of the neocortex. PD is characterized by Lewy bodies with high neuronal dropout in the substantia nigra (SN). DLB is characterized by cortical as well as subcortical Lewy bodies and more widespread neuronal loss. Biochemically, AD is characterized by plaques which are aggregations of amyloid beta protein (Aβ), and tangles which are aggregations of tau. DLB and PD are characterized by Lewy bodies and Lewy neurites, which are aggregations of alpha-synuclein (αSyn). The extent of clinical overlap reflects the extent to which these pathological hallmarks are simultaneously expressed in given cases. Why do these aggregates occur in the first place, and why does their development overlap? As far as AD is concerned, the amyloid cascade hypothesis is the most generally accepted as the initiating cause. It holds that accumulations of Aβ are primarily responsible for AD, with failure to clear it being responsible for wild type disease, and overproduction being responsible for familial disease. According to the hypothesis tau accumulations are secondary. This concept is buttressed by the identification of gene mutations in APP, PS-1 and PS-2, which enhance Aβ production and which result in autosomal dominant AD (reviewed by Hardy, 2006). On the other hand, mutations in tau promote fronto-temporal dementia with parkinsonian features (reviewed by Hutton, 2001) but not Aβ deposits. While this is strong evidence that Aβ accumulation promotes tau accumulation rather than the reverse, it does not explain a mechanism by which Aβ could promote tau accumulation, nor does it account for the distinctive march of tangle development in AD. For the PD/DLB complex, an αSyn burden hypothesis might be proposed. In this hypothesis, wild type PD results from a declining
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P.L. McGeer, E.G. McGeer / Experimental Neurology 212 (2008) 235–238
ability to clear αSyn, while familial disease results either from overproduction of normal αSyn, mutations in αSyn that retard clearance, or mutations in other proteins that assist in αSyn clearance. Evidence in favor of the αSyn burden hypothesis is that mutations resulting in 3 copies of normal αSyn cause PD with typical onset in the fifties (Chartier-Harlin et al., 2004), while those resulting in 4 copies cause PD with typical onset in the thirties (Singleton et al., 2003). The attractiveness of the αSyn burden hypothesis is that it predicts PD and DLB can be eliminated by agents that will reduce the production of αSyn or block its aggregation. Mutations in αSyn promote PD as do proteins such as parkin which may be associated with its functions (Moszczynska et al., 2007). Mutations causing PD were recently reviewed by Gasser (2007). It might be anticipated that AD and the PD/DLB complex would be mutually exclusive disorders given the separate nature of the initial clinical symptoms, the preferential localization of the fundamental pathology, and the differing genetic linkages. In such a case AD and the PD/DLB complex should occur together in a given individual no more frequently than by chance. But the facts are far different. Clinically and pathologically, there is a striking overlap between the two syndromes. Investigators have long noted a clinical association of dementia with PD. Lewy himself reported in 1923 that 64% of the PD patients he examined suffered from dementia (Lewy, 1923). Mjones et al. (1989) reported dementia to occur in 40% of PD patients; Pollock and Hornabrook (1966) 20%; Celesia and Wanabaker (1972) 40%; Marttila and Rinne (1976) 29%; and Lieberman et al. (1979) 20%. Data collected since the more sophisticated clinical and pathological methods of the 1980′s were developed show a comparable association. Aarsland et al. (1996, 2005) extensively reviewed the results of later studies on the prevalence of dementia in PD and reported the proportion to average 24.5%. In summary, there are consistent data stretching over 8 decades of clinical observation indicating that PD patients are highly vulnerable to dementia with a prevalence that may be as much as six times that of an age matched general population (Emre et al., 2007). Are those with AD vulnerable to PD? Fewer quantitative studies have been done, possibly because the typical onset of AD occurs at a later age than PD. (Morris et al., 1989) followed 44 subjects with established AD for a 66 month period. Sixteen (36%) developed PD. In that study, nigral pathology consistent with PD was identified in 80% of the AD cases. Leverenz and Sumi (1986) reported on the pathology of 40 consecutive cases of AD and found that 18 (45%) had neurodegenerative changes in the SN and 11 were consistent with a diagnosis of PD. One pathological study showed that the majority of extrapyramidal signs in AD cases could be attributed to tau brain stem pathology rather than αSyn pathology although both were observed (Attems et al., 2007). Their combined appearance in some cases was taken as confirmation of previous studies of synergistic fibrillization of tau and αSyn (Giasson et al., 2003; Lee et al., 2004). In summary, these studies indicate that the pathological process of PD drives that of AD while that of AD may drive PD. However they give little information on the type of pathology which can drive such overlapping results. More detailed studies are obviously required. The most sophisticated study carried out to date is that reported by Obi et al., 2008. They analyzed by immunohistochemistry the pathological accumulations of αSyn, Aβ and tau in 18 patients with neocortical DLB type pathology compared with 18 patients with AD type pathology. The areas examined were the hippocampus and adjacent temporal cortex. By using sensitive antibodies to αSyn phosphorylated at serine 129 (p αSyn), they identified a far more widespread distribution of αSyn deposits than had previously been suspected to occur in such patients. These additional deposits were in the form of threads and dots which were not detected with αSyn antibodies that were not sensitive to this phosphorylated epitope.
Saito et al. (2003) had pioneered the field by analyzing for αSyn deposits using p αSyn specific antibodies. In addition to the previously identified Lewy bodies and Lewy neurites, they found threads, dots and even diffuse cytoplasmic staining in 25.5% of serial autopsy cases dying from a variety of causes. Those suffering from dementia had the most abundant deposits. They concluded that if the αSyn pathology commenced in the medulla, it led to PD or a DLB transitional form, but if it commenced in the amygdala, it became associated with AD and possibly other tauopathies. The series reported by Obi et al. is instructive in revealing that of the 36 AD and DLB cases chosen on the basis of pathological diagnosis, there were at least 10 that had been misclassified by clinical diagnosis. As far as Lewy body–Lewy neurite pathology in the amygdala was concerned, it appeared in 9 of the cases with a pathological diagnosis of AD in addition to all of those with a pathological diagnosis of DLB. These results illustrate the shortcomings of clinical diagnoses, as well as the limitations of pathological diagnoses, in understanding these overlapping entities. Only two of the 18 DLB cases of Obi et al. lacked Aβ plaques and therefore could be defined as pure DLB. Significant Aβ positive plaques appeared in the remaining DLB cases and all the AD type cases. Obi et al. did a quantitative analysis of the temporal neocortex in all their cases. They found that the sum of αSyn and tau neurite pathology was proportional to the total Aβ burden. The authors have put forward an intriguing hypothesis to explain their results. They propose that Aβ is a key molecule, capable of accelerating a pathological process which can induce either αSyn or tau to aggregate. The final result in any given case depends on the relative propensity of either tau or αSyn to do so. An important observation is that not all αSyn deposits are phosphorylated. Those deposits associated with plaques in typical AD cases were not detected by phosphorylation dependent antibodies. They were only detected by phosphorylation independent antibodies. This complicates any quantitative analysis and it also indicates that αSyn aggregation is not restricted to phosphorylated αSyn. The authors point out that their overall result, namely that AD and DLB pathology frequently overlap, is consistent with at least eleven previous papers which they cite. The degree of overlap varies according to the study and the brain areas examined. To date, the consensus of the literature seems to be that classical AD is the most common entity amongst the dementias, with mixed AD and DLB pathology representing a significant minority of cases, and with pure DLB without AD pathology representing only a small minority of cases. Determining absolute numbers will require further studies. Obi et al. also demonstrated colocalization of αSyn and tau in the temporal lobe of some of their cases. Although this was found only sporadically, it does suggest that αSyn and tau may promote each other's self aggregation without the mediation of Aβ. Such occasional neuronal colocalization has also been reported in the parkinsonism dementia complex of Guam (Yamazaki et al., 2000; Forman et al., 2002), and in cases of the A53T αSyn mutation (Duda et al., 2002), Ishizawa et al. (2003) found codeposition of αSyn and tau in some Lewy bodies of the medulla, locus ceruleus and basal nucleus of Meynert in a small series of cases that included AD, DLB, fronto-temporal dementia and progressive supranuclear palsy. Colocalization of αSyn and tau has also been reported in oligodendroglial cells in multiple system atrophy. This synucleinopathy differs from the PD/DLB complex in that the αSyn deposits are primarily glial rather than neuronal. In summary, it can be said that αSyn and tau may mutually influence self aggregation (reviewed by Galpern and Lang, 2006), but the interaction must be weaker than with Aβ. It is still a mystery as to why Aβ, αSyn and tau, in the process of their own self aggregation, should influence the self aggregation of the others. Obi et al. propose that since Aβ is considered to drive the aggregation of tau, it might similarly be considered to drive the aggregation of αSyn. But the reverse may also hold true. A significant
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proportion of PD cases go on to develop dementia. This would suggest that aggregation of αSyn may be a primary force, capable of driving the aggregation of Aβ and to a lesser extent the aggregation of tau. This possibility escalates the importance of determining what causes the aggregation of αSyn and devising ways of preventing it. Possible mechanisms underlying its aggregation in human tissue and its relationship to PD have recently been reviewed by Beyer and Ariza (2007) and Halliday and McCann (2008). It has been suggested that αSyn is actually neuroprotective and that its aggregation into Lewy bodies is a defense mechanism. However evidence of toxicity of αSyn aggregation is much more powerful than evidence of neuroprotection even if the mechanism by which it produces toxicity is unknown (reviewed by Cookson and van der Brug, 2008). Therapeutic strategies have been reviewed by Amer et al. (2006). Animal models for testing such strategies have been reviewed by Chesselet (2008). To summarize this extensive literature very briefly, there is overwhelming evidence that αSyn aggregation is toxic, especially to dopaminergic neurons of the SN. Beyond the evidence of excess production and possible deficient clearance, there is no clear evidence as to why it aggregates. Specific therapeutic strategies to deal with αSyn aggregation so far are mostly based on specific blockers. A similar strategy is being pursued for Aβ along with strategies to limit production by inhibiting key enzymes and even by enhancing its clearance through vaccination. As for tau aggregation, blockers are also being explored along with strategies aimed at limiting its phosphorylation or enhancing its dephosphorylation. A success in limiting the aggregation of any one of the three molecules might, because of the overlapping phenomenon, be beneficial in limiting aggregation of the others. There is another possible approach to limiting simultaneously the toxic effects of all three aggregators. That is to block the inflammation they appear to induce. αSyn, Aβ and tau are each secreted molecules which can be detected in the CSF. Each, when aggregated, is an inflammatory stimulant in vitro. Since inflammation puts neurons under stress, such stress could be an aggregation inducer. It has been known for some years that aggregated Aβ and tau can induce a toxic inflammatory response but it is only recently that αSyn has also been demonstrated to do so. Thus Zhang et al. (2005) found that αSyn, when oligomerized in vitro, activated microglial cells which were then toxic to cultured dopaminergic neurons. αSyn and its disease causing mutants were shown to upregulate the inflammatory mediators ICAM-1 and IL-6 in astrocytes (Klegeris et al., 2006). In vivo, it is well known that there is a prominent inflammatory reaction in affected brain regions in both AD and PD, suggesting that this reaction may play a major role in the progressive neurodegeneration which takes place. In turn, this has led to the hypothesis that antiinflammatory drugs may delay or slow progression of both diseases. In the case of AD, more than 20 epidemiological studies have appeared over the past 15 years indicating a protective effect of antiinflammatory agents in general, and NSAIDs in particular (reviewed by McGeer and McGeer, 2007). Following the initial study of Chen et al. (2003), epidemiological studies are now beginning to appear showing a protective effect of NSAIDs against PD (reviewed by Esposito et al., 2007) and gene polymorphisms in IL-1beta and TNFalpha have been reported to be risk factors for PD (Wahner et al., 2007). It has also been demonstrated that a plethora of inflammatory mediators are generated by AD and PD by microglia, astrocytes, and even neurons. This includes, but is by no means limited to, inflammatory cytokines, complement proteins, free radicals, anaphylotoxins, and various proteases. The suggestion is that inflammation, however triggered, leads to a neuronal response which not only damages neurons but sustains or even exacerbates the inflammation. The data and their implications have been exhaustively covered in numerous recent reviews (Barcia et al., 2003; Eikelenboom and Van
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Gool, 2004; Hirsch et al., 2005; Hunot and Hirsch 2003; McGeer and McGeer, 2008; Tansey et al., 2007; Whitton, 2007). The essence is that antiinflammatory therapy holds great promise for treating AD and PD. Spreading of the inflammation, with consequent induction of aggregation in molecules prone to do so, might explain the overlapping effects and lead to new routes of therapy. Clinicians and their patients are in desperate need of new therapeutic agents. They are acutely aware of the limitations of currently approved treatments for AD and the PD/DLB complex. Such treatments are based on neurotransmitter enhancement. None of them are directed at the underlying pathological process. As a consequence, they cannot be expected to deal with the overlap syndrome. For example, levodopa and dopamine agonists, which are effective in enhancing dopamine and treating the symptoms of PD, have produced no observable reduction in the accompanying dementia, which appears to have remained relatively constant over eight decades. In AD, cholinesterase inhibitor treatment, designed to enhance the action of acetylcholine, has proved to be of limited value. It should be recalled that, before the advent of levodopa, cholinergic blockers were the most effective treatment for PD. Those cholinergic blockers of the pre-levodopa era, and the cholinesterase inhibitors of the current AD era may rely on broader effects than simple inhibition or enhancement of acetylcholine activity. Nevertheless these are the main actions and they suggest that opposite neurotransmitter drugs are indicated to treat the symptoms of PD and AD while synergistic ones are needed to deal with the overlapping pathologies. Of course drugs that target neurotransmitters do not deal with the underlying pathology which must be the focus of future therapeutic advances. Clinicians can be hopeful for the future, given that much attention is now being paid to attacking the biochemical pathology rather than the neurotransmitter abnormalities they create. Summary In summary, the discovery of αSyn as a causative factor for PD has opened up a productive new area of research. Since PD and DLB have the same biochemical pathology, there would be a better understanding if the disease problem was simply referred to as the PD/DLB complex. The causation of the complex appears to be overproduction of αSyn, or failure in its clearance. This is the basis of the αSyn burden hypothesis. If the hypothesis is correct, inhibiting the production of αSyn, or preventing its aggregation, should lead to the elimination of PD/DLB. It should also ameliorate AD to the extent that αSyn aggregates are a contributing factor. Careful neuropathological studies have shown that aggregations of αSyn, Aβ and tau appear in the same neuronal structures, providing a pathological basis for the clinical observations of the overlap between PD/DLB and AD. The most recent study by Obi et al. (2008) represents an important advance because they have shown that, in cases with a pathological diagnosis of either DLB or AD, the sum of αSyn and tau aggregates are proportional to the Aβ plaque burden. They propose that aggregates of Aβ can promote aggregation of both αSyn and tau with the proportion being determined by the relative susceptibilities of the two to aggregate in any given case. This may not be the complete story since PD drives dementia suggesting that αSyn may be able to drive Aβ aggregation and, to a lesser extent, tau aggregation. Aggregated αSyn, Aβ and tau are all inflammatory stimulants in vitro. Inflammation is a characteristic of both PD and AD and epidemiological studies show that NSAIDs protect against both conditions. It is therefore possible that inflammatory stress on neurons is a promoter of aggregation of all three molecules and that antiinflammatory agents could have broad spectrum effects. Due to the overlapping phenomenon, it might also be anticipated that a therapeutic agent that limited the aggregation of any one of these three molecules would also have some ability to inhibit aggregation of the others.
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Contents lists available at ScienceDirect
Experimental Neurology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y e x n r
Commentary
The α-synuclein burden hypothesis of Parkinson disease and its relationship to Alzheimer disease Patrick L. McGeer ⁎, Edith G. McGeer Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C., Canada V6T 1Z3
A R T I C L E
I N F O
Article history: Received 31 January 2008 Revised 7 April 2008 Accepted 7 April 2008 Available online 20 April 2008
Over the past 8 decades, clinicians have observed that Parkinson disease (PD) patients frequently become demented as their disease progresses. The definition of diffuse Lewy body disease (DLB) as a contributing cause of dementia has opened up a new, and largely unsolved relationship between this more recently described entity, and the classical entities of Parkinson disease (PD) and Alzheimer disease (AD). The clinical as well as the pathological findings of these three entities overlap. Together, they are by far the most common neurodegenerative diseases associated with aging and vigorous research into their causation is a major health priority. They are inexorably progressive, slowly destroying selective areas of the brain in the absence of such conventional causes of neuronal death as infection, neoplasia, malnutrition and vascular insufficiency. In their early stages, they have quite different clinical and pathological manifestations. PD is characterized by deficits in movement with intact cognition, while AD is characterized by deficits in cognition with intact movement. DLB is in between, with cognitive and motor deficits being intertwined. The early cognitive deficits of DLB can be distinguished from those of AD since they frequently involve visual hallucinations and fluctuating attention rather than loss of short term memory. To distinguish DLB as a distinct entity, international meetings of experts have been held to draw up consensus clinical criteria for labeling cases as DLB or simply PD with dementia (McKeith et al., 2005; Emre et al., 2007). An arbitrary rule has emerged which is to define DLB as a disease where dementia appears within 1 year of the development of motor symptoms, whereas PD with dementia is where the onset of dementia takes longer than a year. Such a division is obviously artificial, and since no biochemical distinctions have been identified, it is hard to escape the conclusion that these are manifestations of a single disease entity.
⁎ Corresponding author. Fax: +1 604 822 7086. E-mail address: [email protected] (P.L. McGeer). 0014-4886/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2008.04.008
From an etiological point of view it might appropriately be referred to as the PD/DLB complex even though clinical distinctions will continue to be made. Such a general designation should help to focus efforts on developing new therapeutic agents that will deal with the underlying pathology. Pathologically, AD is characterized by plaques and tangles with high neuronal dropout in the paleocortex and selective areas of the neocortex. PD is characterized by Lewy bodies with high neuronal dropout in the substantia nigra (SN). DLB is characterized by cortical as well as subcortical Lewy bodies and more widespread neuronal loss. Biochemically, AD is characterized by plaques which are aggregations of amyloid beta protein (Aβ), and tangles which are aggregations of tau. DLB and PD are characterized by Lewy bodies and Lewy neurites, which are aggregations of alpha-synuclein (αSyn). The extent of clinical overlap reflects the extent to which these pathological hallmarks are simultaneously expressed in given cases. Why do these aggregates occur in the first place, and why does their development overlap? As far as AD is concerned, the amyloid cascade hypothesis is the most generally accepted as the initiating cause. It holds that accumulations of Aβ are primarily responsible for AD, with failure to clear it being responsible for wild type disease, and overproduction being responsible for familial disease. According to the hypothesis tau accumulations are secondary. This concept is buttressed by the identification of gene mutations in APP, PS-1 and PS-2, which enhance Aβ production and which result in autosomal dominant AD (reviewed by Hardy, 2006). On the other hand, mutations in tau promote fronto-temporal dementia with parkinsonian features (reviewed by Hutton, 2001) but not Aβ deposits. While this is strong evidence that Aβ accumulation promotes tau accumulation rather than the reverse, it does not explain a mechanism by which Aβ could promote tau accumulation, nor does it account for the distinctive march of tangle development in AD. For the PD/DLB complex, an αSyn burden hypothesis might be proposed. In this hypothesis, wild type PD results from a declining
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ability to clear αSyn, while familial disease results either from overproduction of normal αSyn, mutations in αSyn that retard clearance, or mutations in other proteins that assist in αSyn clearance. Evidence in favor of the αSyn burden hypothesis is that mutations resulting in 3 copies of normal αSyn cause PD with typical onset in the fifties (Chartier-Harlin et al., 2004), while those resulting in 4 copies cause PD with typical onset in the thirties (Singleton et al., 2003). The attractiveness of the αSyn burden hypothesis is that it predicts PD and DLB can be eliminated by agents that will reduce the production of αSyn or block its aggregation. Mutations in αSyn promote PD as do proteins such as parkin which may be associated with its functions (Moszczynska et al., 2007). Mutations causing PD were recently reviewed by Gasser (2007). It might be anticipated that AD and the PD/DLB complex would be mutually exclusive disorders given the separate nature of the initial clinical symptoms, the preferential localization of the fundamental pathology, and the differing genetic linkages. In such a case AD and the PD/DLB complex should occur together in a given individual no more frequently than by chance. But the facts are far different. Clinically and pathologically, there is a striking overlap between the two syndromes. Investigators have long noted a clinical association of dementia with PD. Lewy himself reported in 1923 that 64% of the PD patients he examined suffered from dementia (Lewy, 1923). Mjones et al. (1989) reported dementia to occur in 40% of PD patients; Pollock and Hornabrook (1966) 20%; Celesia and Wanabaker (1972) 40%; Marttila and Rinne (1976) 29%; and Lieberman et al. (1979) 20%. Data collected since the more sophisticated clinical and pathological methods of the 1980′s were developed show a comparable association. Aarsland et al. (1996, 2005) extensively reviewed the results of later studies on the prevalence of dementia in PD and reported the proportion to average 24.5%. In summary, there are consistent data stretching over 8 decades of clinical observation indicating that PD patients are highly vulnerable to dementia with a prevalence that may be as much as six times that of an age matched general population (Emre et al., 2007). Are those with AD vulnerable to PD? Fewer quantitative studies have been done, possibly because the typical onset of AD occurs at a later age than PD. (Morris et al., 1989) followed 44 subjects with established AD for a 66 month period. Sixteen (36%) developed PD. In that study, nigral pathology consistent with PD was identified in 80% of the AD cases. Leverenz and Sumi (1986) reported on the pathology of 40 consecutive cases of AD and found that 18 (45%) had neurodegenerative changes in the SN and 11 were consistent with a diagnosis of PD. One pathological study showed that the majority of extrapyramidal signs in AD cases could be attributed to tau brain stem pathology rather than αSyn pathology although both were observed (Attems et al., 2007). Their combined appearance in some cases was taken as confirmation of previous studies of synergistic fibrillization of tau and αSyn (Giasson et al., 2003; Lee et al., 2004). In summary, these studies indicate that the pathological process of PD drives that of AD while that of AD may drive PD. However they give little information on the type of pathology which can drive such overlapping results. More detailed studies are obviously required. The most sophisticated study carried out to date is that reported by Obi et al., 2008. They analyzed by immunohistochemistry the pathological accumulations of αSyn, Aβ and tau in 18 patients with neocortical DLB type pathology compared with 18 patients with AD type pathology. The areas examined were the hippocampus and adjacent temporal cortex. By using sensitive antibodies to αSyn phosphorylated at serine 129 (p αSyn), they identified a far more widespread distribution of αSyn deposits than had previously been suspected to occur in such patients. These additional deposits were in the form of threads and dots which were not detected with αSyn antibodies that were not sensitive to this phosphorylated epitope.
Saito et al. (2003) had pioneered the field by analyzing for αSyn deposits using p αSyn specific antibodies. In addition to the previously identified Lewy bodies and Lewy neurites, they found threads, dots and even diffuse cytoplasmic staining in 25.5% of serial autopsy cases dying from a variety of causes. Those suffering from dementia had the most abundant deposits. They concluded that if the αSyn pathology commenced in the medulla, it led to PD or a DLB transitional form, but if it commenced in the amygdala, it became associated with AD and possibly other tauopathies. The series reported by Obi et al. is instructive in revealing that of the 36 AD and DLB cases chosen on the basis of pathological diagnosis, there were at least 10 that had been misclassified by clinical diagnosis. As far as Lewy body–Lewy neurite pathology in the amygdala was concerned, it appeared in 9 of the cases with a pathological diagnosis of AD in addition to all of those with a pathological diagnosis of DLB. These results illustrate the shortcomings of clinical diagnoses, as well as the limitations of pathological diagnoses, in understanding these overlapping entities. Only two of the 18 DLB cases of Obi et al. lacked Aβ plaques and therefore could be defined as pure DLB. Significant Aβ positive plaques appeared in the remaining DLB cases and all the AD type cases. Obi et al. did a quantitative analysis of the temporal neocortex in all their cases. They found that the sum of αSyn and tau neurite pathology was proportional to the total Aβ burden. The authors have put forward an intriguing hypothesis to explain their results. They propose that Aβ is a key molecule, capable of accelerating a pathological process which can induce either αSyn or tau to aggregate. The final result in any given case depends on the relative propensity of either tau or αSyn to do so. An important observation is that not all αSyn deposits are phosphorylated. Those deposits associated with plaques in typical AD cases were not detected by phosphorylation dependent antibodies. They were only detected by phosphorylation independent antibodies. This complicates any quantitative analysis and it also indicates that αSyn aggregation is not restricted to phosphorylated αSyn. The authors point out that their overall result, namely that AD and DLB pathology frequently overlap, is consistent with at least eleven previous papers which they cite. The degree of overlap varies according to the study and the brain areas examined. To date, the consensus of the literature seems to be that classical AD is the most common entity amongst the dementias, with mixed AD and DLB pathology representing a significant minority of cases, and with pure DLB without AD pathology representing only a small minority of cases. Determining absolute numbers will require further studies. Obi et al. also demonstrated colocalization of αSyn and tau in the temporal lobe of some of their cases. Although this was found only sporadically, it does suggest that αSyn and tau may promote each other's self aggregation without the mediation of Aβ. Such occasional neuronal colocalization has also been reported in the parkinsonism dementia complex of Guam (Yamazaki et al., 2000; Forman et al., 2002), and in cases of the A53T αSyn mutation (Duda et al., 2002), Ishizawa et al. (2003) found codeposition of αSyn and tau in some Lewy bodies of the medulla, locus ceruleus and basal nucleus of Meynert in a small series of cases that included AD, DLB, fronto-temporal dementia and progressive supranuclear palsy. Colocalization of αSyn and tau has also been reported in oligodendroglial cells in multiple system atrophy. This synucleinopathy differs from the PD/DLB complex in that the αSyn deposits are primarily glial rather than neuronal. In summary, it can be said that αSyn and tau may mutually influence self aggregation (reviewed by Galpern and Lang, 2006), but the interaction must be weaker than with Aβ. It is still a mystery as to why Aβ, αSyn and tau, in the process of their own self aggregation, should influence the self aggregation of the others. Obi et al. propose that since Aβ is considered to drive the aggregation of tau, it might similarly be considered to drive the aggregation of αSyn. But the reverse may also hold true. A significant
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proportion of PD cases go on to develop dementia. This would suggest that aggregation of αSyn may be a primary force, capable of driving the aggregation of Aβ and to a lesser extent the aggregation of tau. This possibility escalates the importance of determining what causes the aggregation of αSyn and devising ways of preventing it. Possible mechanisms underlying its aggregation in human tissue and its relationship to PD have recently been reviewed by Beyer and Ariza (2007) and Halliday and McCann (2008). It has been suggested that αSyn is actually neuroprotective and that its aggregation into Lewy bodies is a defense mechanism. However evidence of toxicity of αSyn aggregation is much more powerful than evidence of neuroprotection even if the mechanism by which it produces toxicity is unknown (reviewed by Cookson and van der Brug, 2008). Therapeutic strategies have been reviewed by Amer et al. (2006). Animal models for testing such strategies have been reviewed by Chesselet (2008). To summarize this extensive literature very briefly, there is overwhelming evidence that αSyn aggregation is toxic, especially to dopaminergic neurons of the SN. Beyond the evidence of excess production and possible deficient clearance, there is no clear evidence as to why it aggregates. Specific therapeutic strategies to deal with αSyn aggregation so far are mostly based on specific blockers. A similar strategy is being pursued for Aβ along with strategies to limit production by inhibiting key enzymes and even by enhancing its clearance through vaccination. As for tau aggregation, blockers are also being explored along with strategies aimed at limiting its phosphorylation or enhancing its dephosphorylation. A success in limiting the aggregation of any one of the three molecules might, because of the overlapping phenomenon, be beneficial in limiting aggregation of the others. There is another possible approach to limiting simultaneously the toxic effects of all three aggregators. That is to block the inflammation they appear to induce. αSyn, Aβ and tau are each secreted molecules which can be detected in the CSF. Each, when aggregated, is an inflammatory stimulant in vitro. Since inflammation puts neurons under stress, such stress could be an aggregation inducer. It has been known for some years that aggregated Aβ and tau can induce a toxic inflammatory response but it is only recently that αSyn has also been demonstrated to do so. Thus Zhang et al. (2005) found that αSyn, when oligomerized in vitro, activated microglial cells which were then toxic to cultured dopaminergic neurons. αSyn and its disease causing mutants were shown to upregulate the inflammatory mediators ICAM-1 and IL-6 in astrocytes (Klegeris et al., 2006). In vivo, it is well known that there is a prominent inflammatory reaction in affected brain regions in both AD and PD, suggesting that this reaction may play a major role in the progressive neurodegeneration which takes place. In turn, this has led to the hypothesis that antiinflammatory drugs may delay or slow progression of both diseases. In the case of AD, more than 20 epidemiological studies have appeared over the past 15 years indicating a protective effect of antiinflammatory agents in general, and NSAIDs in particular (reviewed by McGeer and McGeer, 2007). Following the initial study of Chen et al. (2003), epidemiological studies are now beginning to appear showing a protective effect of NSAIDs against PD (reviewed by Esposito et al., 2007) and gene polymorphisms in IL-1beta and TNFalpha have been reported to be risk factors for PD (Wahner et al., 2007). It has also been demonstrated that a plethora of inflammatory mediators are generated by AD and PD by microglia, astrocytes, and even neurons. This includes, but is by no means limited to, inflammatory cytokines, complement proteins, free radicals, anaphylotoxins, and various proteases. The suggestion is that inflammation, however triggered, leads to a neuronal response which not only damages neurons but sustains or even exacerbates the inflammation. The data and their implications have been exhaustively covered in numerous recent reviews (Barcia et al., 2003; Eikelenboom and Van
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Gool, 2004; Hirsch et al., 2005; Hunot and Hirsch 2003; McGeer and McGeer, 2008; Tansey et al., 2007; Whitton, 2007). The essence is that antiinflammatory therapy holds great promise for treating AD and PD. Spreading of the inflammation, with consequent induction of aggregation in molecules prone to do so, might explain the overlapping effects and lead to new routes of therapy. Clinicians and their patients are in desperate need of new therapeutic agents. They are acutely aware of the limitations of currently approved treatments for AD and the PD/DLB complex. Such treatments are based on neurotransmitter enhancement. None of them are directed at the underlying pathological process. As a consequence, they cannot be expected to deal with the overlap syndrome. For example, levodopa and dopamine agonists, which are effective in enhancing dopamine and treating the symptoms of PD, have produced no observable reduction in the accompanying dementia, which appears to have remained relatively constant over eight decades. In AD, cholinesterase inhibitor treatment, designed to enhance the action of acetylcholine, has proved to be of limited value. It should be recalled that, before the advent of levodopa, cholinergic blockers were the most effective treatment for PD. Those cholinergic blockers of the pre-levodopa era, and the cholinesterase inhibitors of the current AD era may rely on broader effects than simple inhibition or enhancement of acetylcholine activity. Nevertheless these are the main actions and they suggest that opposite neurotransmitter drugs are indicated to treat the symptoms of PD and AD while synergistic ones are needed to deal with the overlapping pathologies. Of course drugs that target neurotransmitters do not deal with the underlying pathology which must be the focus of future therapeutic advances. Clinicians can be hopeful for the future, given that much attention is now being paid to attacking the biochemical pathology rather than the neurotransmitter abnormalities they create. Summary In summary, the discovery of αSyn as a causative factor for PD has opened up a productive new area of research. Since PD and DLB have the same biochemical pathology, there would be a better understanding if the disease problem was simply referred to as the PD/DLB complex. The causation of the complex appears to be overproduction of αSyn, or failure in its clearance. This is the basis of the αSyn burden hypothesis. If the hypothesis is correct, inhibiting the production of αSyn, or preventing its aggregation, should lead to the elimination of PD/DLB. It should also ameliorate AD to the extent that αSyn aggregates are a contributing factor. Careful neuropathological studies have shown that aggregations of αSyn, Aβ and tau appear in the same neuronal structures, providing a pathological basis for the clinical observations of the overlap between PD/DLB and AD. The most recent study by Obi et al. (2008) represents an important advance because they have shown that, in cases with a pathological diagnosis of either DLB or AD, the sum of αSyn and tau aggregates are proportional to the Aβ plaque burden. They propose that aggregates of Aβ can promote aggregation of both αSyn and tau with the proportion being determined by the relative susceptibilities of the two to aggregate in any given case. This may not be the complete story since PD drives dementia suggesting that αSyn may be able to drive Aβ aggregation and, to a lesser extent, tau aggregation. Aggregated αSyn, Aβ and tau are all inflammatory stimulants in vitro. Inflammation is a characteristic of both PD and AD and epidemiological studies show that NSAIDs protect against both conditions. It is therefore possible that inflammatory stress on neurons is a promoter of aggregation of all three molecules and that antiinflammatory agents could have broad spectrum effects. Due to the overlapping phenomenon, it might also be anticipated that a therapeutic agent that limited the aggregation of any one of these three molecules would also have some ability to inhibit aggregation of the others.
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