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Age and Ageing Advance Access originally published online on April 27, 2006
Age and Ageing 2006 35(4):332-335; doi:10.1093/ageing/afl009
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© The Author 2006. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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Alzheimer therapeutics—what after the cholinesterase inhibitors?

Lary C. Walker1,2 and Rebecca F. Rosen1

1 Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA
2 Department of Neurology, Emory University, Atlanta, GA 30322, USA

Address correspondence to: L. C. Walker. Email: lary.walker{at}emory.edu


   The first generation of Alzheimer therapeutics
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 The first generation of...
The proteopathic basis of...
 The next generation of...
 The road ahead
 References
 
In the 1970s and early 1980s, biochemical and neuropathological evidence emerged, implicating the degeneration of basal forebrain acetylcholinergic neurons in Alzheimer’s disease (AD) [1]. The ‘cholinergic hypothesis’ of AD held that cholinergic dysfunction causes cognitive decline and that dementia therefore might be mitigated by the augmentation of acetylcholine activity in brain. The logical therapeutic objective was to boost the levels of the transmitter by inhibiting its catabolic enzyme, acetylcholinesterase. Today, several cholinesterase inhibitors are marketed for the treatment of mild-to-moderate dementia. They have been demonstrated to improve, relative to placebo, various cognitive and functional capacities [2], and there is evidence that they may slow the pathogenesis of AD [3]. Additionally, an inhibitor of ionotropic neurotransmitter receptors (memantine) recently was approved for use in moderate-to-severe dementia [4]. However, because multiple neuronal systems are severely damaged in AD, the benefits of agents that selectively target the activity of certain transmitters are small. The limitations of the current generation of AD therapies led, in 2005, to a tentative proposal by the National Institute of Clinical Excellence (NICE) not to recommend donepezil, rivastigmine, galantamine or memantine for the treatment of dementia (provisional recommendation of the cholinesterase inhibitors for moderate dementia has since been reinstated; the final recommendations are due in July 2006 [5]). Although these drugs offer hope, and probably some benefit, to many patients, the improvements are modest and mainly symptomatic, and the patients and their families must eventually face the reality that the drugs cannot halt the relentless deterioration of mental capacities. Fortunately, recent research on the fundamental pathogenesis of AD reveals promising new strategies for arresting or preventing the disease.


   The proteopathic basis of neurodegenerative diseases
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 The first generation of...
 The proteopathic basis of...
The next generation of...
 The road ahead
 References
 
A century ago this year, Alois Alzheimer first described unusual lesions in the autopsied brain of a demented patient, including the deposits of a ‘peculiar substance’ in the cerebral parenchyma and odd, tangled fibrils within nerve cells [6]. We now know that the ‘peculiar substance’ is an aggregated, fibrillar form of the ß-amyloid protein (Aß), which forms the cores of senile plaques, and that the neurofibrillary tangles consist of abnormally polymerised tau protein. For unknown reasons, Aß and tau undergo a conformational conversion that renders the proteins prone to self-aggregation into plaques and tangles, respectively [7, 8]. Interestingly, multiple disorders of the brain and systemic organs entail the aberrant accumulation of disease-specific proteins, suggesting that diverse protein conformational disorders, or ‘proteopathies’, share similar pathogenic mechanisms [7].

By convention, an abundance of plaques and tangles in a patient with dementia is diagnostic of AD, but how the lesions contribute to the signs and symptoms of AD has been controversial. Although tauopathy is vital for the clinical manifestations of AD [9], genetic and clinicopathological findings indicate that tau dysfunction is downstream of Aß in the proteopathic cascade. Specifically, all known risk factors for AD augment the production and/or accumulation of Aß in brain [8]. Hence, most current research into the arrest or prevention of AD centres on Aß, although tau is undoubtedly a viable therapeutic target, both for AD and other tauopathies [10, 11]. Importantly, a growing body of data supports the view that small, soluble oligomeric forms of Aß are the main toxic agents, rather than the amyloid fibrils that comprise the cores of senile plaques [12, 13]. Preventing the formation or toxicity of these Aß oligomers may be the ultimate key to halting the progression of AD pathogenesis.


   The next generation of Alzheimer therapeutics: targeting the Aß cascade
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 The first generation of...
 The proteopathic basis of...
 The next generation of...
The road ahead
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Currently, the most compelling approach to treating AD is based on the hypothesis that the build-up and pathogenicity of Aß are fundamental to the progression of the disease. At some point, other pathological events become part of the cascade, including tauopathy and inflammation. The centrality of Aß in this process suggests several disease-modifying strategies: (i) block the cellular production of Aß, (ii) prevent the self-assembly of Aß, (iii) promote the catabolism of Aß, (iv) stimulate the removal of Aß and (v) counteract the cytotoxicity of multimeric Aß.

Block the production of Aß
Beta-amyloid precursor protein (ßAPP) usually is cleaved within the Aß sequence by the enzyme {alpha}-secretase, which splits Aß, rendering it non-amyloidogenic. Alternative cleavages by ß-secretase (ß-amyloid cleaving enzyme, or BACE) and {gamma}-secretase at the Aß N- and C-termini, respectively, yield monomeric Aß. Most pharmacological efforts to reduce the production of Aß have been directed towards inhibiting ß- or {gamma}-secretase [14]. Experimental evidence confirms the therapeutic potential of this approach [15, 16], but developing safe and effective inhibitors of the secretases has been challenging. {gamma}-Secretase is an intramembranous enzyme complex that also is critical for cleaving (and thereby activating) the transmembrane receptor/signalling protein Notch; blocking {gamma}-secretase lowers Aß formation in experimental systems, but reducing Notch activity could interfere with important cellular proliferation and differentiation pathways [17]. In this regard, R-flurbiprofen (FlurizanTM), the R-enantiomer of the anti-inflammatory agent flurbiprofen, selectively lowers Aß42 production via allosteric modulation of {gamma}-secretase activity [18], preserving the activity of {gamma}-secretase on Notch and other substrates. The agent is well tolerated, and limited efficacy recently was reported in mild, but not moderate, AD subjects [19]. More study of this strategy is warranted [20], but one implication of the clinical findings is that early treatment will be critical to reaping optimal benefit from disease-modifying therapies.

Unlike {gamma}-secretase, direct inhibition of ß-secretase (BACE) appears to be comparatively safe in animal models, but the open binding pocket of ß-secretase has thus far thwarted the development of potent, small molecule inhibitors [21]. Neutralising Aß by enhancing {alpha}-secretase cleavage also is a plausible, if complicated, anti-Aß tactic [22], and there is evidence that statins, which might reduce the risk of AD, act in this manner [23].

Prevent the self-assembly of Aß
A second option is to interfere with the aggregation of Aß into oligomeric and/or fibrillar assemblies [24]. Tramiprosate (AlzhemedTM), a glycosaminoglycan mimetic developed to block the interactions of proteoglycans with amyloid fibrils and thereby impede amyloid aggregation, has been reported to reduce senile plaque load in a mouse model of ß-amyloidosis [25]. Tramiprosate recently reached phase III clinical trials [25], the results of which will help determine the potential of aggregation inhibition in AD. Although theoretically attractive, impeding protein–protein interactions can be difficult pharmacologically [7]. Additionally, it may be necessary to interrupt the Aß self-assembly process very early in the cascade, as inhibiting fibril formation conceivably could cause the accumulation of prefibrillar oligomers and thereby exacerbate cytotoxicity.

Promote the catabolism of Aß
Aß can be broken down by endopeptidases, notably neprilysin and insulin-degrading enzyme (IDE) [26]. Increasing the activity of these enzymes in ßAPP-transgenic mice reduces brain Aß levels and senile plaque load [27]. Thus, pharmacological augmentation of Aß-degrading enzyme function in the brain is an encouraging means by which one might slow the course of AD. However, selective up-regulation of enzymatic activity can be problematic, and it is important to be mindful of other substrates that might be adversely affected. For these reasons, blocking the enzymatic liberation of Aß remains a more attractive Aß-lowering approach.

Stimulate the removal of Aß
An auspicious strategy for halting AD pathogenesis is to promote the elimination of Aß, either immunologically or by enhancing the transcellular efflux of the peptide from the brain. Anti-Aß immunisation reduces Aß load and improves behavioural performance in ßAPP-transgenic mice [28] and even has shown hints of disease-modifying efficacy in early AD [29, 30]. Unforeseen adverse events, particularly aseptic meningoencephalitis, have hindered the clinical application of Aß-immunotherapy in AD [31], but the effectiveness of immunisation in preclinical models justifies the current intensity of research in this arena.

Aß is a substrate for certain cellular transport systems, including LRP1 [32] and p-glycoprotein (Pgp) [33]. Pgp insufficiency in particular has been linked to a higher cerebral Aß load [34, 35]. Several available drugs are known to enhance Pgp activity in humans; however, the functional importance of transporters in various organs suggests that their up-regulation should be undertaken cautiously.

Block the cytotoxicity of multimeric Aß
How multimers of Aß exert their cytopathic effects remains uncertain, although two possibilities that have surfaced are abnormal interactions of globular oligomers [36] with cellular elements, or the formation of membrane pores that act as anomalous ion channels [37]. If the production, assembly and elimination of Aß prove to be refractory to the development of effective therapies, the downstream effects of Aß aggregation on cell integrity represent another option. For instance, should Aß pores be proven to form in membranes of degeneration-prone cells, selective Aß-channel-blocking agents could be useful AD therapeutics.


   The road ahead
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 The first generation of...
 The proteopathic basis of...
 The next generation of...
 The road ahead
References
 
The next generation of AD therapeutics will be judged by their ability to provide more than temporary, symptomatic relief from the dementia of Alzheimer’s disease. The burgeoning data implicating aberrant Aß in the genesis of AD argue for a sustained and diversified research effort in this domain. Alzhemed and Flurizan, which specifically (if incompletely) target the Aß cascade, are at the vanguard of potentially disease-modifying, small-molecule therapies for AD. Basic and clinical research on Aß immunisation and direct secretase inhibition, perhaps the most promising approaches, also is proceeding apace. A conspicuous void in our knowledge is a fuller understanding of the in vivo conditions that favour the initial corruption and propagation of Aß, i.e. the ‘prime mover’ of the Aß cascade. Several potentially tractable factors have been inculpated in the early pathogenesis of AD, including inflammation, oxidative stress, as well as changes in pH, temperature and metal-ion homeostasis [38–40]. Elucidation of the contribution of these factors to the Aß cascade is a significant objective that could open alternative pathways to disease-modifying therapies for AD and other degenerative proteopathies.


   References
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 The first generation of...
 The proteopathic basis of...
 The next generation of...
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