Alzheimer's disease: Aβ, tau and synaptic dysfunction

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Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by two hallmark lesions: extracellular amyloid plaques and neurofibrillary tangles. The role that these lesions have in the pathogenesis of AD has proven difficult to unravel, in part because of unanticipated challenges of reproducing both pathologic hallmarks in transgenic mice. Recent advances in recapitulating both plaques and tangles in the brains of transgenic mice are leading to novel insights into their role in the degenerative process, including their impact on synaptic activity and plasticity. Transgenic mice that harbor both neuropathological lesions are also facilitating the elucidation of the relationship of these proteinaceous aggregates to one another and providing a crucial in vivo system for developing and evaluating therapies.

Introduction

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and the most common cause of dementia among the elderly. The clinical symptoms of AD include memory loss, particularly of recent events during the initial phases, and impairments in other cognitive domains that interfere with mood, reason, judgment and language. Eventually, even simple tasks, such as maintaining personal hygiene, cannot be performed and the patient becomes completely socially dependent. Age is the major risk factor for dementia, with a doubling of risk every five years after the age of 65 [1]. By the middle of the century, the prevalence of AD in the USA is projected to almost quadruple, such that one in every 45 individuals will be afflicted [1]. The disease course is insidious and AD patients might live up to 20 years after the initial diagnosis, although the median survival is between five and ten years [2]. Because current therapies do not abate the underlying disease process, it is likely that AD will continue to be a clinical, social and economic burden for some time.

Most forms of AD are sporadic (i.e. idiopathic), with the onset of symptoms generally beginning after 65–70 years of age. A small proportion of cases, however, exhibit a Mendelian pattern of inheritance and are referred to as familial Alzheimer's disease (FAD). Mutations in three different genes, APP and presenilin-1 and -2 (PS1 and PS2), are known to cause FAD 3, 4, 5, which is typically characterized by the development of clinical symptoms with an early onset (<65 years of age). Neuropathologically, both FAD and sporadic AD are remarkably similar and are characterized by two hallmark proteinaceous aggregates: amyloid plaques and neurofibrillary tangles (Figure 1). Amyloid plaques are compact, spherical extracellular deposits consisting of a small (∼4 kDa) protein called the amyloid β-peptide (Aβ) [6]. These extracellular lesions are usually found in limbic brain regions, such as the hippocampus and amygdala, and also in specific cortical and subcortical areas. Most plaques in the AD brain are of the diffuse type, containing or surrounded by few dystrophic dendrites and axons, in contrast to the less frequent neuritic plaques, in which dystrophic neurites are a prominent and commonplace feature. Neurofibrillary tangles are intracellular aggregates that are composed of hyperphosphorylated forms of the tau protein 7, 8. These filamentous inclusions occur in select neuronal cell bodies. In addition to these proteinaceous aggregates, the AD brain is also marked by additional neuropathological alterations, including the loss of synapses, atrophy, the selective depletion of neurotransmitter systems (e.g. acetylcholine) and by Lewy bodies in a minority of cases 9, 10.

Section snippets

Role of Aβ in Alzheimer's disease

The Aβ peptide, which is the primary protein component of diffuse and neuritic plaques, originates through proteolysis from the amyloid-precursor protein (APP; Figure 2). The function of the APP holoprotein is not yet established and mice lacking the APP gene show relatively minor neurological impairments 11, 12. This subtle phenotype is probably due to compensatory effects mediated by two other members of the APP gene family: amyloid-precursor-like protein-1 and -2 (APLP1 and APLP2) [13]. This

Role of tau in neurodegeneration

Neurofibrillary tangles are filamentous inclusions that accumulate in selective neurons in the brains of individuals with AD, but they also occur in other neurodegenerative disorders, including frontal temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The major component of tangles is the microtubule-associated protein tau 7, 8. In its normal state, tau is a soluble protein that

Modeling plaques and tangles in transgenic mice

Generating mice with both plaques and tangles is crucial for studies of the molecular relationship between Aβ and tau and to test the effectiveness that anti-AD interventions have on both pathologies. To make a model that better mimics AD neuropathology, a novel approach was used that involved co-microinjecting two transgenes (encoding APPswe and tauP301L under the control of the Thy1.2 promoter) into single-cell embryos harvested from PS1M146V KI mice [31]. The resulting mice are

Evidence linking Aβ and tau pathology

The amyloid-cascade hypothesis stipulates that Aβ is the trigger of all cases of AD and that the tau pathology and other degenerative changes are a downstream consequence of the Aβ pathology [17]. Based on this hypothesis, therefore, the introduction of mutant APP or PS genes into mice should trigger a wide spectrum of AD neuropathology. Although mutant APP or APP and PS1 mice develop extensive amyloid deposits, surprisingly, this has proven insufficient to trigger other key aspects of AD

Synaptic dysfunction in AD

Modeling both plaques and tangles in AD-relevant brain regions enables one to establish the relationship of these proteinaceous structures to crucial neurologic processes, such as learning and memory, synaptic plasticity and brain inflammation. Recent work indicates that spatial and contextual learning and memory is affected in the 3xTg-AD mice in an age-dependent manner and, notably, the onset of cognitive deficits occurs in advance of overt plaque and tangle pathology and is caused by the

Cell loss

Perhaps the last major hurdle that needs to be adequately addressed is the role of neuronal loss in mouse models of AD. Generally, APP-transgenic mice show little to no evidence of any cell loss, although one APP model results in significant loss 47, 48, 49, 50, 51, 52. By contrast, transgenic mice that overexpress Aβ1–42 show fairly robust cell loss [53]. Notably, some of the tau transgenic mice show cell loss, suggesting that neurofibrillary pathology might be a requisite for neuronal loss 37

Concluding remarks

The development of mouse models of AD is evolving and with each generation more closely mimics the major neuropathology. This progress will probably bode well for better understanding the disease mechanism. For example, the mechanism underlying the interaction between amyloid and tangle pathologies in AD remains to be elucidated and genetically altered mice, such as the 3xTg-AD model, are providing valuable molecular tools for addressing this crucial question. In addition, transgenic mice that

Acknowledgements

This work was supported by grants from the National Institutes of Health (AG0212982). We thank Drs Kim Green and Lauren Billings for critically reading the manuscript.

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