Trends in Molecular Medicine
Alzheimer's disease: Aβ, tau and synaptic dysfunction
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.
References (58)
- et al.
Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein
Biochem. Biophys. Res. Commun.
(1984) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments
J. Biol. Chem.
(1986)Behavioral and anatomical deficits in mice homozygous for a modified β-amyloid precursor protein gene
Cell
(1994)β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity
Cell
(1995)Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms
Neuron
(1992)Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding
Neuron
(1993)Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding
Neuron
(1993)Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease
Neuron
(1989)Phylogenetic diversity of the expression of the microtubule-associated protein tau: implications for neurodegenerative disorders
Brain Res. Mol. Brain Res.
(1999)Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction
Neuron
(2003)
Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease
Neurobiol. Aging
Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins
Neuron
Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration
Neuron
Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome
Neuron
Reduced levels of Aβ 40 and Aβ 42 in brains of smoking controls and Alzheimer's patients
Neurobiol. Dis.
Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset
Am. J. Public Health
Survival of outpatients with Alzheimer-type dementia
Ann. Intern. Med.
Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene
Nature
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease
Nature
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Nature
Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau
Proc. Natl. Acad. Sci. U. S. A.
Plaque-only Alzheimer disease is usually the lewy body variant, and vice versa
J. Neuropathol. Exp. Neurol.
Interactions of amyloidogenic proteins
Neuromolecular Med.
Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid β protein precursor
Proc. Natl. Acad. Sci. U. S. A.
Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members
J. Neurosci.
Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease
Nat. Med.
Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer's disease
Proc. Natl. Acad. Sci. U. S. A.
The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
Science
Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology
Proc. Natl. Acad. Sci. U. S. A.
Cited by (383)
CRISPR/Cas9 system and its applications in nervous system diseases
2024, Genes and DiseasesCell-free RNA signatures predict Alzheimer's disease
2023, iScienceIdentification of Mild cognitive impairment based on quadruple GCN model constructed with multiple features from higher-order brain connectivity
2023, Expert Systems with ApplicationsTREM2: Potential therapeutic targeting of microglia for Alzheimer's disease
2023, Biomedicine and PharmacotherapyAmygdala activity and amygdala-hippocampus connectivity: Metabolic diseases, dementia, and neuropsychiatric issues
2023, Biomedicine and Pharmacotherapy