Alzheimer Disease: Florida

Golde TE. · Mayo Clinic College of Medicine, Department of Neuroscience, Mayo Clinic Jacksonville 4500 San Pablo Road., Jacksonville, Florida 32224, USA. · J Neurochem. · Pubmed #17076654 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of dementia in industrialized nations. If more effective therapies are not developed that either prevent AD or block progression of the disease in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Only two types of drugs are currently approved for the treatment of AD: inhibitors of acetyl cholinesterase, which symptomatically enhance cognitive state to some degree but are not disease modifying; and the adamantane derivative, memantine. Memantine preferentially blocks excessive NMDA receptor activity without disrupting normal receptor activity and is thought to be a neuroprotective agent that blocks excitotoxicty. Memantine therefore may have a potentially disease modifying effect in multiple neurodegenerative conditions. An improved understanding of the pathogeneses of AD has now led to the identification of numerous therapeutic targets designed to alter amyloid beta protein (Abeta) or tau accumulation. Therapies that alter Abeta and tau through these various targets are likely to have significant disease modifying effects. Many of these targets have been validated in proof of concept studies in preclinical animal models, and some potentially disease modifying therapies targeting Abeta or tau are being tested in the clinic. This review will highlight both the promise of and the obstacles to developing such disease modifying AD therapies.

Eriksen JL, Janus CG. · Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Behav Genet. · Pubmed #17072762 No free full text.

Abstract: Within the past decade, our understanding of the pathogenic mechanisms in Alzheimer's disease (AD) has dramatically advanced because of the development of transgenic mouse models that recapitulate the key pathological and behavioral phenotypes of the disease. These mouse models have allowed investigators to test detailed questions about how pathology develops and to evaluate potential therapeutic approaches that could slow down the development of this disease. In this review, we discuss the status of transgenic mouse models and review the complex relationship between pathology and behavior in the development of neuropathological syndromes in AD.

Dickey CA, Petrucelli L. · Mayo Clinic Jacksonville, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Expert Opin Ther Targets. · Pubmed #16981824 No free full text.

Abstract: The pathological hallmarks of Alzheimer's disease (AD) include abnormal intra- and extraneuronal tau and amyloid accumulation, respectively, accompanied by gliosis, oxidative stress and neuron loss. The discovery of mutations within the tau gene itself that cause clinical dementia (i.e., fronto-temporal dementia with Parkinsonism linked to chromosome 17 [FTDP17]) demonstrated that disruption of normal tau function independent of amyloidogenesis was sufficient to cause neuronal loss and clinical dementia. These studies demonstrate the need for therapeutics that either decrease the total pool of tau or selectively reduce aberrant forms of tau (i.e., hyperphosphorylated, misfolded etc.). To this point, therapeutic development for tauopathies, including AD, have primarily focused on either the phosphorylation of tau, as it is a downstream target for many kinases and signalling cascades, or inhibition of tau aggregation. Recent developments, however, suggest that pharmacological targeting of other mechanisms may hold therapeutic promise for the treatment of tauopathies.

Sugaya K, Alvarez A, Marutle A, Kwak YD, Choumkina E. · Biomolecular Sciences Center, Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32816-2364, USA. · Panminerva Med. · Pubmed #16953146 No free full text.

Abstract: We have found much evidence that the brain is capable of regenerating neurons after maturation. In our previous study, human neural stem cells (HNSCs) transplanted into aged rat brains differentiated into neural cells and significantly improved the cognitive functions of the animals, indicating that HNSCs may be a promising candidate for cell-replacement therapies for neurodegenerative diseases including Alzheimer's disease (AD). However, ethical and practical issues associated with HNSCs compel us to explore alternative strategies. Here, we report novel technologies to differentiate adult human mesenchymal stem cells, a subset of stromal cells in the bone marrow, into neural cells by modifying DNA methylation or over expression of nanog, a homeobox gene expressed in embryonic stem cells. We also report peripheral administrations of a pyrimidine derivative that increases endogenous stem cell proliferation improves cognitive function of the aged animal. Although these results may promise a bright future for clinical applications used towards stem cell strategies in AD therapy, we must acknowledge the complexity of AD. We found that glial differentiation takes place in stem cells transplanted into amyloid-( precursor protein (APP) transgenic mice. We also found that over expression of APP gene or recombinant APP treatment causes glial differentiation of stem cells. Although further detailed mechanistic studies may be required, RNA interference of APP or reduction of APP levels in the brain can significantly reduced glial differentiation of stem cells and may be useful in promoting neurogenesis after stem cell transplantation.

Mortimer JA, Borenstein AR. · Department of Epidemiology and Biostatistics, University of South Florida, 13201 Bruce B. Downs Blvd., Tampa, FL 33612, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16917193 No free full text.

Abstract: This review provides a summary of epidemiologic tools to facilitate understanding of the design and analysis of studies of Alzheimer disease (AD) and related disorders. Proportions, ratios, rates, prevalence, incidence, study designs, bias, confounding, effect modification, odds and risk ratios, statistical power, and confidence intervals are defined and discussed. Descriptive epidemiology is concerned with describing the distribution of disease by person, place, and time. It is useful for hypothesis generation, but not generally for hypothesis testing. Observational analytic epidemiology focuses on identifying putative causes for an illness. Although its primary mission is hypothesis testing, it can lead to new hypotheses as well. Finally, experimental analytic epidemiology or clinical trials can provide rigorous tests of presumed causal associations. The strengths and limitations of various designs as they apply to determining causal associations in studies of AD and dementia are reviewed. Over the past 60 years, the epidemiologic study of dementia has evolved from basic descriptive studies of prevalence and incidence to case-control and cohort studies and finally to the first clinical trials to prevent AD.

Morgan D. · Alzheimer Research Laboratory, Department of Pharmacology and Molecular Therapeutics, University of South Florida, Tampa, FL 33612, USA. · J Alzheimers Dis. · Pubmed #16914881 No free full text.

Abstract: A primary goal of research on Alzheimer's disease is to develop disease modifying therapeutics. The amyloid cascade hypothesis has focused the initial efforts on methods to reduce amyloid. One surprising approach that has shown considerable success in mouse models and has hinted at benefits in human trials is anti-Abeta immunotherapy. Schenk first showed the amyloid reducing potential of active immunization in 1999. This prompted our group and that of St. George-Hyslop to investigate whether active immunization would similarly retard the memory deficits that develop in amyloid depositing transgenic mice. Contrary to our initial predictions of premature memory dysfunction due to inflammation, vaccination protected amyloid depositing mice from developing memory deficits. Subsequent studies found that passive immunization could reverse memory deficits, even when administered for short periods. These encouraging findings led to a trial of an Abeta vaccination in Alzheimer patients. The trial was cut short due to meningoencephalitic symptoms in 6% of patients, yet, in a subset of patients, those developing brain reactive antibodies benefited from slower rates of cognitive decline. These observations have accelerated the development of passive immunization protocols and safer vaccines. At this time, anti-amyloid immunotherapy stands poised to be the first test of the amyloid hypothesis in the treatment of Alzheimer disease.

Morgan D. · Alzheimer Research Laboratory, Department of Pharmacology and Molecular Therapeutics, University of South Florida, MDC Box 9, Tampa, FL 33612, United States. · Neurochem Int. · Pubmed #16740342 No free full text.

Abstract: Alzheimer's disease is a large and growing health problem. Several lines of transgenic mice overexpressing the amyloid precursor protein (APP) develop both diffuse and compacted amyloid deposits which increase in size and number with age. In the vicinity of compacted deposits, these mice develop neuritic dystrophy and activation of glia. Ultimately, these mice also develop memory deficits. Immunotherapy against the Abeta peptide has been effective in both clearing amyloid deposits from the brain, and improving the mnemonic performance of the transgenic mice. Associated with these actions, are changes in the expression of microglial markers. In some cases, the glial activation markers decline, consistent with reduced provocation from amyloid deposits. However, in a time course study, we found that some markers of microglial activation increase transiently once the immunotherapy is initiated. Still another marker continues to rise for up to 3 months of treatment, and remains elevated even after the parenchymal amyloid deposits are largely removed. These changes are consistent with a shift in the microglial phenotype, transitioning from a condition associated with inflammation and ineffective in clearing Abeta deposits to one with reduced inflammation, and capable of clearing deposited amyloid.

McGowan E, Eriksen J, Hutton M. · Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Trends Genet. · Pubmed #16567017 No free full text.

Abstract: It has been over a decade since the first Alzheimer's disease (AD) transgenic mouse models were reported. These models have enabled dramatic advances in our understanding of the pathogenic mechanism in AD and of potential therapeutic approaches to tackling the inexorable clinical progression of the disease. In this article, we discuss the current status of AD mouse models and focus on recent work that has examined the development of the neuropathological lesions observed in AD (plaques and tangles). The relationship between these lesions, neurodegeneration and development of the clinical syndrome will be explored.

Borenstein AR, Copenhaver CI, Mortimer JA. · Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa, FL 33612, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16493239 No free full text.

Abstract: Research findings obtained over the past 20 years suggest that Alzheimer disease (AD) may have its origins in early life. In this review, we consider the evidence for early-life risk factors for this illness. We propose that risk factors that predict neuropathology are largely distinct from those related to the clinical expression of Alzheimer disease. Early-life risk factors for pathology include genes, chromosomal abnormalities, head injury, insulin resistance, and inflammation. With regard to risk factors for clinical expression of Alzheimer disease, six general groups of childhood exposures are reviewed: (1) perinatal conditions, (2) early-life brain development, (3) early-life body growth, (4) early-life socioeconomic conditions, (5) environmental enrichment, and (6) cognitive reserve. The literature reviewed suggests that risk of Alzheimer disease is probably not determined in any single time period but results from the complex interplay between genetic and environmental exposures throughout the life course. Enhancement or preservation of brain or cognitive reserve could delay the onset of Alzheimer disease and in some cases prevent the disease from occurring altogether.

Vandeweerd C, Paveza GJ, Fulmer T. · The James and Jennifer Harrell Center for the Study of Family Violence, Department of Community and Family Health, College of Public Health, University of South Florida, 13301 Bruce B Downs Boulevard, MDC 56, Tampa, FL 33620, USA. · Nurs Clin North Am. · Pubmed #16492453 No free full text.

Abstract: Elder mistreatment is a serious issue that effects the lives of thousands of older adults and results in emotional difficulties, such as depression,feelings of inadequacy, self-loathing, and lowered self-esteem. It has been shown to result in family distress, impaired life functioning, and difficulties with cognition and has been linked to health problems,such as immunologic dysfunction, and increased mortality. As the population ages, and with it the numbers of persons afflicted by diseases such as Alzheimer's, understanding and recognizing elder mistreatment becomes an important factor in maintaining quality of life for older adults.

Balducci L, Ershler WB, Krantz S. · H. Lee Moffitt Cancer & Research Institute, University of South Florida, 12902 Magnolia Dr. Tampa, FL 33612, USA. · Crit Rev Oncol Hematol. · Pubmed #16387511 No free full text.

Abstract: Anemia is common in older people and it becomes more so with advancing decades. Because the older population is increasing, the prevalence of anemia and consequently its impact on health and healthcare expenditure is expected to rise. Although the causes and consequences of anemia have not been fully elucidated and its etiology is occasionally elusive, clinical evidence has indicated that anemia itself is a cause of morbidity and it can complicate other health conditions. The clinical approach to anemia is evolving. In the past, anemia was mainly seen as a sign of underlying disease; today, anemia is considered to be a cause of severe deterioration of quality of life, morbidity, and decline in physical function, and a risk factor for death. A better understanding of anemia in the elderly will lead to improved treatment strategies, including the more judicious use of transfusion and appropriate use of erythropoietic agents.

Mortimer JA, Borenstein AR, Gosche KM, Snowdon DA. · Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa, FL 33612-3899, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16306243 links to  free full text

Abstract: Numerous studies show that the pathology of Alzheimer's disease is present decades before a clinical diagnosis of dementia can be made. Given the likelihood that agents will become available that reliably delay onset and/or slow progression of Alzheimer's disease, it will be important to detect preclinical Alzheimer's disease as early as possible for maximal treatment effect. Detection of individuals by sensitive cognitive measures provides one way to identify people who are at high risk of developing clinical Alzheimer's disease. However, it is likely that those with considerable brain or cognitive reserve will be able to mask cognitive deficits until very close to the onset of the dementia, rendering such cognitive measures insensitive. Optimum biomarkers for Alzheimer's disease therefore need to target the severity of underlying brain pathology independently of brain reserve. Findings are presented showing the importance of higher education and larger brain size in masking the underlying disease pathology.

Streit WJ, Conde JR, Fendrick SE, Flanary BE, Mariani CL. · Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL 32610, USA. · Neurol Res. · Pubmed #16197805 No free full text.

Abstract: Microglial cells comprise a network of endogenous immunocompetent cells that pervade the brain and spinal cord. The primary function of this system is to provide continuous surveillance of the parenchyma and protect the central nervous system (CNS) during injury and disease. Here we discuss the involvement of microglia during brain aging and aging-related neurodegenerative disease, i.e. Alzheimer's disease, and briefly summarize their possible roles in amyotrophic lateral sclerosis (ALS). In addition, we provide an overview of the neuroinflammation associated with primary brain tumors and how microglial tumor cytotoxicity could be targeted for immunotherapeutic approaches designed to treat these lesions.

Morgan D, Gordon MN, Tan J, Wilcock D, Rojiani AM. · Department of Pharmacology, University of South Florida, Tampa, 33612, USA. · J Neuropathol Exp Neurol. · Pubmed #16141783 No free full text.

Abstract: The presence of activated microglia in postmortem Alzheimer disease specimens is used to support the argument that inflammation contributes to Alzheimer pathogenesis. Transgenic mice overexpressing the amyloid precursor protein (APP) gene form amyloid plaques that are accompanied by local activation of microglia/macrophages in a manner similar to the human disease. Many markers of microglial activation and inflammation increase in an age-dependent manner in these mice. However, manipulation of these inflammatory reactions can lead to unexpected outcomes with several instances of reduced pathology when microglia/macrophages are activated further. In particular, anti-Abeta immunotherapy in amyloid-depositing transgenic mice causes a complex series of changes in microglial markers, negating the implicit belief that such activation is monotonic and represented equally well by any of several "activation" markers. A survey of the peripheral macrophage literature identifies at least 2 distinct activation states of macrophages with different consequences for the surrounding tissue. These different activation states can often be distinguished by the markers that are expressed. Several markers are identified from studies outside the brain that neuroscientists might consider evaluating when attempting to more definitively describe the activation state of the monocyte-derived cells in the brain.

Lucas JA. · Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, USA. · Psychiatr Clin North Am. · Pubmed #16122568 No free full text.

Abstract: The understanding of the neuroanatomic substrates and cognitive processes underlying memory functioning has improved dramatically during the past several decades. Animal studies and observations of patients who have brain diseases show that memory is not a unitary factor but instead can be parsed into overlapping but dissociable constructs; that encoding, retention, and retrieval processes depend on the integrity of several distinct brain regions; and that the creation of new memories depends on structural and functional changes within the neuronal systems of those brain regions. Much remains to be learned, however, regarding the specific biologic,genetic, and information-processing mechanisms underlying many features of this complex cognitive construct. As this knowledge base grows, new and improved pharmacologic and behavioral treatments for patients who have memory disorders may be realized.

Dinoto L, Deture MA, Purich DL. · Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610-0245, USA. · Microsc Res Tech. · Pubmed #16104002 No free full text.

Abstract: Although Tau and MAP2 readily assemble into straight filaments (SFs), Tau's unique ability to form paired-helical filaments (PHFs) may offer clues as to why Tau's microtubule-binding region (MTBR) is the exclusive building block of the neurofibrillary tangles that accumulate during Alzheimer's disease. To learn more about the factors permitting Tau to form both SFs and PHFs, we investigated the microtubule binding, thiol oxidation, and polymerization reactions of the monomer and dimer forms of Tau and MAP2 MTBRs. This review focuses on electron microscopic evidence (1) that facilitated the identification of amino acid residues within 3-repeat Tau that promote PHF formation; and (2) provided experimental evidence for the polymerization of S-glutathionylated three-repeat Tau, a reaction that unambiguously demonstrates that disulfide-linked Tau-S-S-Tau dimer formation is not a compulsory step in filament assembly. We also consider these findings within the context of current views on the genetic and biochemical basis of Tau fibrillogenesis.

Sugaya K. · Biomolecular Sciences Center, Burnett College of Biomedical Sciences, University of Central Florida, 4000 Central Florida Blvd., BMS Building, Room 223, Orlando, FL 32816-2364, USA. · Curr Alzheimer Res. · Pubmed #15974902 No free full text.

Abstract: The statement, "neurodegenerative diseases are incurable because neurons do not regenerate during adulthood," has been challenged, and we have now found much evidence that the matured brain is capable of regenerating neurons. In our previous study, human neural stem cells (HNSCs) transplanted into aged rat brains differentiated into neural cells and significantly improved the cognitive functions of the animals, indicating that HNSCs may be a promising candidate for neuro-replacement therapy. However, because of ethical and practical issues associated with HNSCs, development of autologous stem cell strategies may be desired. We established new technologies to differentiate adult human mesenchymal stem cells into neural cells by modifying cell fate decisions. We also found a pyrimidine derivative that increases endogenous stem cell proliferation and neurogenesis after peripheral administrations of this compound. Although these results may promise a bright future for clinical applications of stem cell strategies in Alzheimer's disease (AD) therapy, we must acknowledge the complexity of AD. For example, abnormal metabolism of the amyloid-beta precursor protein (APP) may affect stem cell biology, while the prevalence of amyloid-beta peptide (Abeta) toxicity theory in AD pathology tends to limit our focus on the physiological functions of APP. We found that excess APP in the environment causes glial differentiation of stem cells. Even though the glial activation may be useful to eliminate Abeta deposits, neuronal differentiation of stem cells is needed for replacement of degenerating neurons in the AD brain. Thus, further investigation of the influence of AD pathology on stem cell biology is required.

Flanary B. · Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32610-0244, USA. · Rejuvenation Res. · Pubmed #15929715 No free full text.

Abstract: With each cell division, telomeres progressively shorten until they reach a critical length, at which point the cells enter cellular senescence. Microglia, a non-neuronal cell type residing within the central nervous system (CNS), play vital roles in maintaining neuronal function, health, and survival in both the normal and pathological CNS. A recent article described an increased incidence of microglial cytoplasmic structural abnormalities (i.e., swelling, twisted and shortened processes, and fragmentation) and dystrophy occurring in the cerebral cortex of human brains with age. These results suggest that microglial dystrophy may be a result of, or contribute to, their senescence, which in turn may impair their neuron-sustaining functions and ultimately lead to neuronal cell death.

Streit WJ. · Department of Neuroscience, University of Florida College of Medicine, Gainesville, 32610-0244, USA. · Brain Res Brain Res Rev. · Pubmed #15850662 No free full text.

Abstract: The first part of this paper summarizes some of the key observations from experimental work in animals that support a role of microglia as neuroprotective cells after acute neuronal injury. These studies point towards an important role of neuronal-microglial crosstalk in the facilitation of neuroprotection. Conceptually, injured neurons are thought to generate rescue signals that trigger microglial activation and, in turn, activated microglia produce trophic or other factors that help damaged neurons recover from injury. Against this background, the second part of this paper summarizes recent work from postmortem studies conducted in humans that have revealed the occurrence of senescent, or dystrophic, microglial cells in the aged and Alzheimer's disease brain. These findings suggest that microglial cells become increasingly dysfunctional with advancing age and that a loss of microglial cell function may involve a loss of neuroprotective properties that could contribute to the development of aging-related neurodegeneration.

Golde TE. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA. · Brain Pathol. · Pubmed #15779241 No free full text.

Abstract: 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.

Golde TE, Janus C. · Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. · Neuron. · Pubmed #15748837 No free full text.

Abstract: In this issue of Neuron, a study by Billings et al. points to intracellular Abeta as a possible cause of neuronal dysfunction. In a mouse model of Alzheimer's disease, Billings et al. link appearance of intraneuronal Abeta to cognitive impairments and then show that "clearance" of intraneuronal Abeta by anti-Abeta antibodies restores cognitive deficits.

Crocco EA, Loewenstein DA. · Department of Psychiatry, Mount Sinai Medical Center, 4300 Alton Road, MRI Building, 2nd Floor, Miami Beach, FL 33140, USA. · Curr Psychiatry Rep. · Pubmed #15717983 No free full text.

Abstract: Mild cognitive impairment in the elderly may represent a transitional phase between normal aging and early Alzheimer's disease (AD). It recently has been recognized as a distinct clinical entity with potentially different cognitive subtypes and etiologies. Like AD, studies have shown that psychiatric symptoms are more common than in the cognitively normal geriatric population. Understanding these symptoms has been recognized as important not only because they may impair patient function and caregiver burden, but also these symptoms may be relevant to understanding the development of AD in general. This article presents current information on psychiatric symptoms in mild cognitive impairment, their suggested role in the pathophysiology of AD and future research considerations on the subject.

Glueckauf RL, Ketterson TU, Loomis JS, Dages P. · Department of Medical Humanities and Social Sciences, College of Medicine, Florida State University, Tallahassee, Florida, USA. · Telemed J E Health. · Pubmed #15319052 No free full text.

Abstract: Family caregivers of older adults with progressive dementia (e.g., Alzheimer's disease) are confronted with a variety of challenges in providing assistance to their loved ones, such as dealing with persistent, repetitive questions, managing episodes of agitation and aggressive responding, as well as monitoring hygiene and self-care activities. Although professional and governmental organizations have called for the creation of community-based education and support programs, a significant proportion of dementia caregivers in the United States continue to receive little or no formal instruction in responding effectively to these anxiety-provoking situations. This paper describes the development and implementation of Alzheimer's Caregiver Support Online (also known as AlzOnline), an Internet- and telephone-based education and support network for caregivers of individuals with progressive dementia. An outcome analysis of a Robert Wood Johnson Foundation-funded strategic marketing initiative to promote the use of AlzOnline is reviewed, followed by a presentation of the findings of an initial program evaluation. Finally, future directions for online caregiver evaluation research are proposed.

Hutton M, McGowan E. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. · Neuron. · Pubmed #15294135 No free full text.

Abstract: The report by Oddo and colleagues in this issue of Neuron demonstrates for the first time that clearance of amyloid also results in the removal of early-stage tau pathology in mice that develop both amyloid plaques and neurofibrillary tangles (NFT), the two hallmark lesions of Alzheimer's disease (AD). This result supports a primary role for Abeta in AD etiology.

Dickson DW. · Department of Pathology, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA. · J Clin Invest. · Pubmed #15232608 links to  free full text

Abstract: Increasing evidence suggests that selective neuronal loss in neurodegenerative diseases involves activation of cysteine aspartyl proteases (caspases), which initiate and execute apoptosis. In Alzheimer disease both extracellular amyloid deposits and intracellular amyloid beta protein may activate caspases, leading to cleavage of nuclear and cytoskeletal proteins, including tau protein. Proteolysis of tau may be critical to neurofibrillary degeneration, which correlates with dementia.