Rational heterodoxy: Cholesterol reformation of the amyloid doctrine

According to the amyloid cascade hypothesis, accumulation of the amyloid peptide Aβ, derived by proteolytic processing from the amyloid precursor protein (APP), is the key pathogenic trigger in Alzheimer's disease (AD). This view has led researchers for more than two decades and continues to be the most influential model of neurodegeneration. Nevertheless, close scrutiny of the current evidence does not support a central pathogenic role for Aβ in late-onset AD. Furthermore, the amyloid cascade hypothesis lacks a theoretical foundation from which the physiological generation of Aβ can be understood, and therapeutic approaches based on its premises have failed.We present an alternative model of neurodegeneration, in which sustained cholesterol-associated neuronal distress is the most likely pathogenic trigger in late-onset AD, directly causing oxidative stress, inflammation and tau hyperphosphorylation. In this scenario, Aβ generation is part of an APP-driven adaptive response to the initial cholesterol distress, and its accumulation is neither central to, nor a requirement for, the initiation of the disease. Our model provides a theoretical framework that places APP as a regulator of cholesterol homeostasis, accounts for the generation of Aβ in both healthy and demented brains, and provides suitable targets for therapeutic intervention.     

Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer's disease

SIGNIFICANCE: Mitochondria and brain bioenergetics are increasingly thought to play an important role in Alzheimer's disease (AD). RECENT ADVANCES: Data that support this view are discussed from the perspective of the amyloid cascade hypothesis, which assumes beta-amyloid perturbs mitochondrial function, and from an opposite perspective that assumes mitochondrial dysfunction promotes brain amyloidosis. A detailed review of cytoplasmic hybrid (cybrid) studies, which argue mitochondrial DNA (mtDNA) contributes to sporadic AD, is provided. Recent AD endophenotype data that further suggest an mtDNA contribution are also summarized. CRITICAL ISSUES AND FUTURE DIRECTIONS: Biochemical, molecular, cybrid, biomarker, and clinical data pertinent to the mitochondria-bioenergetics-AD nexus are synthesized and the mitochondrial cascade hypothesis, which represents a mitochondria-centric attempt to conceptualize sporadic AD, is discussed.     

"Emerging Alzheimer's disease therapies: focusing on the future"

The Center for Neurodegenerative Disease Research (CNDR) organized a 1 day symposium entitled "Emerging Alzheimer's disease Therapies: Focusing On The Future" on November 7th, 2001 at the University of Pennsylvania in Philadelphia, PA. The agenda (Fig. 1) focused on novel therapies for Alzheimer's disease (AD) designed to prevent/eliminate Abeta deposits in the brains of AD patients. While fibrillar Abeta deposits known as senile plaques (SPs) and intraneuronal tau fibrils known as neurofibrillary tangles (NFTs) are diagnostic of AD, >50% of patients with familial or sporadic AD as well as elderly Down's syndrome patients with AD harbor a third type of brain amyloid known as Lewy bodies formed by intraneuronal alpha-synuclein fibrils. Thus, AD is a "triple brain amyloidosis" since three different proteins (tau, alpha-synuclein) or peptide fragments (Abeta) of a larger Abeta precursor protein (APP) fibrillize and aggregate into pathological deposits of amyloid within (NFTs, LBs) and outside (SPs) neurons in AD brains. The symposium is summarized here followed by reviews from symposium speakers who describe potential anti-Abeta therapies some of which are in clinical trials.     

The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease

In recent years the amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly referred to as the amyloid beta protein (Abeta) cascade hypothesis. This subtle rephrasing reflects the acknowledgment that there is debate within the field as to whether Abeta aggregates other than Abeta deposited as classic amyloid fibrils could trigger the pathological cascade that results in neuronal dysfunction and neurodegeneration. Despite this semantic shift, which highlights one enigmatic aspects of AD, the evidence supporting the Abeta hypothesis of AD is extensive. More importantly the Abeta hypothesis of AD has led and will continue to lead to the development of rationale therapeutic strategies that are likely to either prevent or treat this devastating disease. In this review, the evidence supporting the Abeta hypothesis and the recent advances in anti-Abeta therapy are discussed.     

On the origin of Alzheimer's disease. Trials and tribulations of the amyloid hypothesis

The amyloid cascade hypothesis, which implicates the amyloid Aβ peptide as the pathological initiator of both familial and sporadic, late onset Alzheimer's disease (AD), continues to guide the majority of research. We believe that current evidence does not support the amyloid cascade hypothesis for late onset AD. Instead, we propose that Aβ is a key regulator of brain homeostasis. During AD, while Aβ accumulation may occur in the long term in parallel with disease progression, it does not contribute to primary pathogenesis. This view predicts that amyloid-centric therapies will continue to fail, and that progress in developing successful alternative therapies for AD will be slow until closer attention is paid to understanding the physiological function of Aβ and its precursor protein.     

Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia, increasing in prevalence with age. Most patients who develop AD have an unknown cause, but characteristic neuropathological features include the deposition of extracellular amyloid beta and of intraneuronal hyperphosphorylated tau protein. Researchers have previously implicated mitochondrial dysfunction in AD. We previously showed an increase in neurons displaying a mitochondrial biochemical defect-cytochrome-c oxidase (COX) deficiency-in the hippocampus in patients with sporadic AD compared with age-matched controls. COX deficiency is well described as a marker of mitochondrial (mt) DNA dysfunction. This present study analyzed the mtDNA in single neurons from both COX normal and COX-deficient cells. Analysis of the mtDNA revealed that COX deficiency is caused by high levels of mtDNA deletions which accumulate with age. Future research is needed to clarify the role mtDNA deletions have in normal aging and investigate the relationship between mtDNA deletions and the pathogenesis of sporadic AD.     

Herpesviral infections and antimicrobial protection for Alzheimer's disease: Implications for prevention and treatment

Accumulating evidence suggests that infections by herpesviruses might be closely linked to Alzheimer's disease (AD). Pathological hallmarks of AD brains include senile plaques induced by amyloid β peptide (Aβ) in the extracellular space and intracellular neurofibrillary tangles (NFTs) consisting of phosphorylated tau protein. The prevailing hypothesis for the mechanism of AD is amyloid cascade reaction. Recent studies revealed that infections by herpesviruses induce the similar pathological hallmarks of AD, including Aβ production, phosphorylation of tau (P-tau), oxidative stress, neuroinflammation, etc. Aβ peptide is regarded as one of the antimicrobial peptides, which inhibits HSV-1 replication. In the elderly, reactivation of herpesviruses might act as an initiator for amyloid cascade reaction in vulnerable individuals, triggering the neurofibrillary formation of phosphorylated tau and inducing oxidative stress and neuroinflammation, which can further contribute to the accumulation of Aβ and P-tau by impairing mitochondria and autophagosome. Epidemiological studies have shown AD susceptibility genes, such as APOE-ε4 allele, are highly linked to infections by herpesviruses. Interestingly, anti-herpesviral therapy significantly reduced the risk of AD in a large population study. Given that herpesviruses are arguably the most prevalent opportunistic pathogens and often reactivate in the elderly, it is reasonable to argue reactivation of herpesviruses might be major culprits for initiating AD in individuals carrying AD susceptibility genes. In this review, we summarize epidemiological and molecular evidence that support for a hypothesis of herpesviral infections and antimicrobial protection in the development of AD, and discuss the implications for future prevention and treatment of the disease.     

Analysis of premature centromere division (PCD) of the chromosome 18 in peripheral blood lymphocytes in Alzheimer disease patients

Premature centromere division (PCD) of the chromosome 18 was analyzed by using fluorescent in situ hybridization (FISH) on interphase peripheral blood lymphocytes isolated from six sporadic Alzheimer disease (AD) patients and six healthy elderly controls. Results of FISH analysis revealed that chromosome 18 expressed PCD in 5.18% interphase nuclei of AD patients, and in 2.59% interphase nuclei of age-matched controls (p<0.05). Our study also showed that hypoploidy and hyperploidy frequency for chromosome 18 exhibited a statistically significant increase in the AD group compared to the control one. The increase in spontaneous aneuploidy of chromosome 18 in AD patients which is correlated with PCD shows that deregulation of the time of centromere separation can be considered as a manifestation of chromosome instability leading to aneuploidy.     

Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau

Molecular genetic analysis is revealing the etiologies of Alzheimer's disease (AD) and related dementias. Here we review genetic and molecular biological evidence suggesting that the peptide A beta 42 is central to the etiology of AD. Recent data also suggests that dysfunction in the cytoskeletal protein tau is on the pathway that leads to neurodegeneration and dementia. Tau is produced either indirectly, by A beta 42, or directly, in some forms of frontotemporal dementia by mutations in tau itself. These data support are refine the amyloid cascade hypothesis for AD and suggest that understanding the causes and consequences of tau dysfunction is an important priority for dementia research.     

Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer's disease brain

Neurofibrillary tangles (NFT), intracellular inclusions of abnormal fibrillar forms of microtubule associated protein tau, accumulate in Alzheimer's disease (AD) and other tauopathies and are believed to cause neuronal dysfunction, but the mechanism of tau-mediated toxicity are uncertain. Tau overexpression in cell culture impairs localization and trafficking of organelles. Here we tested the hypothesis that, in the intact brain, changes in mitochondrial distribution occur secondary to pathological changes in tau. Array tomography, a high-resolution imaging technique, was used to examine mitochondria in the reversible transgenic (rTg)4510, a regulatable transgenic, mouse model and AD brain tissue. Mitochondrial distribution is progressively disrupted with age in rTg4510 brain, particularly in somata and neurites containing Alz50-positive tau aggregates. Suppression of soluble tau expression with doxycycline resulted in complete recovery of mitochondrial distribution, despite the continued presence of aggregated tau. The effect on mitochondrial distribution occurs without concomitant alterations in neuropil mitochondrial size, as assessed by both array tomography and electron microscopy. Similar mitochondrial localization alterations were also observed in human AD tissue in Alz50+ neurons, confirming the relevance of tau to mitochondrial trafficking observed in this animal model. Because abnormalities reverted to normal if soluble tau was suppressed in rTg4510 mice, even in the continued presence of fibrillar tau inclusions, we suggest that soluble tau plays an important role in mitochondrial abnormalities, which likely contribute to neuronal dysfunction in AD.     

Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage

We recently reported increased mitochondrial fission and decreased fusion, increased amyloid beta (Aβ) interaction with the mitochondrial fission protein Drp1, increased mitochondrial fragmentation, impaired axonal transport of mitochondria and synaptic degeneration in neurons affected by AD. In the present study, we extended our previous investigations to determine whether phosphorylated tau interacts with Drp1 and to elucidate mitochondrial damage in the progression of AD. We also investigated GTPase activity, which is critical for mitochondrial fragmentation, in postmortem brain tissues from patients with AD and brain tissues from APP, APP/PS1 and 3XTg.AD mice. Using co-immunoprecipitation and immunofluorescence analyses, for the first time, we demonstrated the physical interaction between phosphorylated tau and Drp1. Mitochondrial fission-linked GTPase activity was significantly elevated in the postmortem frontal cortex tissues from AD patients and cortical tissues from APP, APP/PS1 and 3XTg.AD mice. On the basis of these findings, we conclude that Drp1 interacts with Aβ and phosphorylated tau, likely leading to excessive mitochondrial fragmentation, and mitochondrial and synaptic deficiencies, ultimately possibly leading to neuronal damage and cognitive decline. Treatment designed to reduce the expression of Drp1, Aβ and/or phosphorylated tau may decrease the interaction between Drp1 and phosphorylated tau and the interaction between Drp1 and Aβ, conferring protection to neurons from toxic insults of excessive Drp1, Aβ and/or phosphorylated tau.     

Calcyclin binding protein and Siah-1 interacting protein in Alzheimer's disease pathology: neuronal localization and possible function

The calcyclin binding protein and Siah-1 interacting protein (CacyBP/SIP) protein was shown to play a role in the organization of microtubules. In this work we have examined the neuronal distribution and possible function of CacyBP/SIP in cytoskeletal pathophysiology. We have used brain tissue from Alzheimer's disease (AD) patients and from transgenic mice modeling 2 different pathologies characteristic for AD: amyloid and tau. In the brain from AD patients, CacyBP/SIP was found to be almost exclusively present in neuronal somata, and in control patients it was seen in the somata and neuronal processes. In mice doubly transgenic for amyloid precursor protein and presenilin 1 there was no difference in CacyBP/SIP neuronal localization in comparison with the nontransgenic animals. By contrast in tau transgenic mice, localization of CacyBP/SIP was similar to that observed for AD patients. To find the relation between CacyBP/SIP and tau we examined dephosphorylation of tau by CacyBP/SIP. We found that indeed it exhibited phosphatase activity toward tau. Altogether, our results suggest that CacyBP/SIP might play a role in AD pathology.     

Chromosome studies of patients with Alzheimer disease

Ten patients with either the familial or sporadic form of Alzheimer disease (AD) were studied cytogenetically to confirm reports of aneuploidy and “long acentric fragments” associated with the disease. Findings in leukocytes of patients were compared with those in eight unaffected relatives and seven persons of similar age. Observations from encoded slides involving 3,800 conventionally stained and 1,396 G-banded metaphases (one patient) showed no significant increase in aneuploidy. The frequency of cells with hypermodal counts, a reliable measure of aneuploidy, was 4.2% and 1.1%, respectively, in women and men with familial AD and 4.0% and 2.3%, respectively, in women and men with the sporadic form of the illness. Similar frequencies of hypermodal cells occurred in female (2.6%) and in male (2.0%) control subjects. In contrast to the lack of aneuploidy, a small but significant number of false “long acentric fragments” was found in cells of women with AD (P <.05). These aberrations are thought to represent premature centromere division (PCD) in intact chromosomes, primarily supernumerary Xs. Often in multiple copies, PCD occurred in 2.8% of their cells and in 0.6% of cells from control women. PCD occurred in 3.6% of cells of women with the familial form and in 1.7% of cells of women with the sporadic type of dementia. Among unaffected relatives PCD increased with age. The rarity of PCD in G-banded metaphases from an affected female (3/1,396) suggests that metaphase spreading techniques also may affect observable frequency. Thus PCDs occur more frequently in, but are not unique to, AD and may represent an epiphenomenon of aging, a process also characterized by the occurrence of neurofibrillary tangles and senile plaques in the cerebral cortex.     

Is the pattern of nerve cell loss in aging and Alzheimer's disease a real, or only an apparent, selectivity?

The pattern of neuronal loss from the brain in Alzheimer's disease (AD) is selective, not on the basis of neurotransmitter type, metabolic character or trophic dependence, but only in relationship to the anatomical connection of all affected cell types with the association cortex. The "selectivity" of the process of AD seems to lie with local factors within the cerebral cortex whose presence (or absence) links the processes that lead to the deposition of amyloid (A4) protein, to the neuritic response that results in the production and accumulation of abnormal tau proteins and which, ultimately, form the neurofibrillary tangle and bring about the demise of the neurone.     

Tissue transglutaminase, protein cross-linking and Alzheimer's disease: review and views

Extensive protein cross-linking and aggregation are some of the most common molecular events in the pathogenesis of Alzheimer's disease (AD). Both beta-amyloid (Abeta) plaques and neurofibrillary tangles, which are extracellular and intracellular proteinaceous aggregates, respectively, contribute to neuronal death and progressive cognitive decline. Although protein cross-linking has been recognized and extensively studied for many years, the underlying mechanisms are largely unknown. Recent data indicates that tissue transglutaminase (tTG), which catalyzes the cross-linking of a wide spectrum of proteins including Abeta, tau, alpha-synuclein and neurofilament proteins, may be involved in protein aggregation in AD. Many AD risk factors, such as trauma, inflammation, ischemia and stress, up-regulate tTG protein and activity levels. In this review, we summarize the evidence that tTG plays a role in AD, especially in cross-linking of Abeta, tau, alpha-synuclein and neurofilament proteins. An experimentally testable hypothesis is that tTG may play a central role in AD pathogenesis and that it provides a conceptual link between sporadic and familial AD through a shared pathogenic pathway.     

Lithium may be useful in the prevention of Alzheimer's disease in individuals at risk of presenile familial Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia among older people. Presenile familial AD (FAD) and sporadic Alzheimer's disease (SAD) have identical brain lesions, containing senile plaques with beta-amyloid (Abeta) peptide and neurofibrillary tangles formed by hyperphosphorylation of a microtubule-associated protein known as tau. However, FAD and SAD differ in onset and genetic transmission. Unlike SAD, presenile FAD is transmitted as a pure autosomal dominant trait. The authors suggest that lithium could be used for AD prevention, particularly in individuals at risk of presenile FAD, which has early onset. Evidence supporting this hypothesis suggests that lithium decreases Abeta peptide production and inhibits the activity of glycogen synthase kinase-3 which induces aggregation of tau protein into tangles, and tau hyperphosphorylation. Prevalence of AD is lower in patients with chronic lithium treatment, which also increases brain-derived neurotrophic factor activity, so might prevent onset in patients at risk for AD. Several considerations are suggested for prevention trials: the effect of lithium could be evaluated in young animal models that express presenile FAD mutant genes; the time, dose, duration and monitoring of lithium therapy are considered; early phenotypes could be monitored for treatment effect; and some other agents, like valproic acid, could also be candidates for prevention.     

Familial Alzheimer's disease: genetic influences on the disease process (Review).

Alzheimer's disease (AD) has both genetic and environmental etiologies. Genetic causes include presenilin (PS) mutations on chromosomes 1 and 14, and amyloid precursor protein (APP) mutations on chromosome 21. At least two susceptibility genes also exist. In this review phenotypic differences in AD groups are described and possible differences in the mechanism(s) by which AD mutations lead to dementia are reviewed. Clinical, pathological and biochemical phenotypes distinguish AD cases with different etiologies. For example, age-at-onset and age-at-death between PS-1, PS-2, APP and sporadic AD groups differ. Also, some forms of AD are associated with more Abeta deposition others, and some AD groups have morphologically distinct Abeta deposits or other unique histopathologic features. APP-related AD mutations always occur within the Abeta portion of the APP gene, adjacent to sites where alpha-, beta- and gamma-secretase breakdown pathways operate in the expressed protein. These mutations alter APP metabolism leading to increased Abeta production. It is unknown if other AD groups are subject to identical changes in APP metabolism. Activation of apoptosis pathways, more general defects in protein transport or metabolism, differential regulation of tau kinases or other factors may also be important. Overall, data support the notion that differences occur in the disease process in etiologically distinct AD groups.     

Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia

Nearly all mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid beta precursor protein (APP) genes lead to early-onset Alzheimer disease (EOAD, onset age at or before 65 years). In order to assess the genetic contribution of these genes in a series of Colombian AD cases, we performed a systematic mutation analysis in 11 autosomal dominant, 23 familial, and 42 sporadic AD patients (34% with age of onset < or = 65 years). No APP missense mutations were identified. In three autosomal dominant cases (27.2%), two different PSEN1 missense mutations were identified. Both PSEN1 mutations are missense mutations that occurred in early-onset autosomal AD cases: an I143T mutation in one case (onset age 30 years) and an E280A mutation in two other cases (onset ages 35 and 42 years). In addition, a novel PSEN1 V94M mutation was present in one early-onset AD case without known family history (onset age 53 years) and absent in 53 controls. The E318G polymorphism was present in five AD cases and absent in controls. In PSEN2, two different silent mutations were detected, including one not reported elsewhere (P129). The majority of the Colombian AD cases, predominantly late-onset, were negative for PSEN and APP mutations.     

Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease

Elevated levels of amyloid beta (Aβ) peptide, hyperphosphorylation of tau protein, and inflammation are pathological hallmarks in Alzheimer's disease (AD). Phosphodiesterase 7 (PDE7) regulates the inflammatory response through the cyclic adenosine monophosphate signaling cascade, and thus plays a central role in AD. The aim of this study was to evaluate the efficacy of an inhibitor of PDE7, named S14, in a mouse model of AD. We report that APP/Ps1 mice treated daily for 4 weeks with S14 show: (1) significant attenuation in behavioral impairment; (2) decreased brain Aβ deposition; (3) enhanced astrocyte-mediated Aβ degradation; and (4) decreased tau phosphorylation. These effects are mediated via the cyclic adenosine monophosphate/cyclic adenosine monophosphate response element-binding protein signaling pathway, and inactivation of glycogen synthase kinase (GSK)3. Our data support the use of PDE7 inhibitors, and specifically S14, as effective therapeutic agents for the prevention and treatment of AD.