Alzheimer's Disease: A Century of Scientific and Clinical Research
A-F | G-H | I-L | M-Q | R-S | T-Z
GSK-3 Is Essential in the Pathogenesis of Alzheimer’s Disease
Abstract: Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3ß is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3ß has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3ßwas involved in amyloid ß(Aß-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional investigations showing that Aß activates GSK-3ß through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Aß-activated GSK-3ß induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3ß can induce memory deficits in vivo; and that inhibition of GSK-3alpha (an isoform of GSK-3ß) reduces Aß production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease.
Robert D. Terry
My own experience in early research on Alzheimer disease
This brief paper reviews the work on dementia by the Neuropathology group at the Einstein College of Medicine and later at the University of California, San Diego, from the time of our first approaches to Alzheimer Disease in 1959. The electron microscope studies concerned the tangle (got it wrong) and then the plaque (got it right). Lysosomes and active mitochondria were noted in the plaques. Axoplasmic transport was suggested to be abnormal. We studied the plaques in old dogs and old monkeys, and then went on to use image analysis to count neurons in the neocortex of Alzheimer cases and in examples of normal aging. Later in San Diego we quantified presynaptic boutons and recognized their loss as the major direct cause of dementia. Many collaborators including Henry Wisniewski participated in these early attempts to understand the disease.
Virginia M.-Y. Lee, John Q. Trojanowski
Progress From Alzheimer’s Tangles To Pathological Tau Points Towards More Effective Therapies Now
Abstract: The landmark description of neurofibrillary tangles (NFTs) and senile plaques as the pathological hallmarks of an unusual form of dementia 100 years ago by Alois Alzheimer launched the quest to understand a neurodegenerative disorder that now has become a scourge in the 21st Century due to the unprecedented increase in human life expectancy since 1900. Indeed, while there are many benefits to individuals and society as a whole that will accrue from the remarkable gains in longevity since 1900, the risk of developing Alzheimer’s disease (AD) increases exponentially with advancing age beyond the 7th decade of life. Hence, the prevalence of AD will rise inexorably in the coming decades unless effective interventions are developed to delay the onset or progression of AD. Widespread international recognition of the urgency of this problem has accelerated research to discover meaningful therapies for AD, and growing evidence implicates impairments of axonal transport in mechanisms underlying AD due to pathological alterations in tau, the building block proteins of NFTs. This brief review summarizes insights into mechanisms whereby pathological alterations in tau impair axonal transport resulting in neurodegeneration and how these insights are being exploited now to develop novel therapeutic interventions for the treatment of AD.
Christine Van Broeckhoven, Samir Kumar-Singh
Genetics and Pathology of Alpha-Secretase Site AßPP Mutations in Understanding of Alzheimer’s disease
Abstract: Development of therapeutics begins with delineating the precise disease pathology along with a reasonable understanding of the sequence of events responsible for the development of disease, or disease pathogenesis. For Alzheimer’s disease (AD), the classical pathology is now known for quite some time; however, the disease pathogenesis has eluded our understanding for a complete century. This review, in addition to providing a brief overview of all primary events, will highlight those aspects of AD genetics and novel pathological descriptions linked to unique mutations within AßPP that have led to our better understanding of the pathogenesis of AD. Specifically, we will discuss how pathologies linked to the Dutch (E693Q) and Flemish AßPP (A692G) mutations have helped in understanding the role of CAA in dementia and the development of dense-core plaques. In addition, this review will also point directions that warrant additional studies.
F.W.van Leeuwen, E.M. Hol, D.F. Fischer
Frameshift proteins in Alzheimer’s disease and in other conformational disorders: time for the ubiquitin-proteasome system
Abstract: Neuronal homeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the ubiquitin-proteasome system (UPS) and discovered a frameshift protein for ubiquitin (UBB+1), that accumulates in the neuritic plaques and tangles in patients with Alzheimer’s disease (AD). UBB+1, unable to tag proteins to be degraded, has been shown to be a substrate for ubiquitination and subsequent proteasomal degradation. If UBB+1 is accumulated, it inhibits the proteasome, which may result in neuronal death. We showed that UBB+1 is also present in other tauopathies (e.g. Pick’s disease) and in several polyglutamine diseases, but remarkably not in synucleinopathies (e.g. Parkinson’s disease). Accumulation of UBB+1 -being a reporter for proteasomal dysfunctioning- thus differentiates between these conformational diseases. The accumulation of UBB+1 causes a dysfunctional UPS in these multifactorial neurodegenerative diseases. Novel transgenic mouse models and large-scale expression profiling and functional analyses of enzymes of the UPS compounds –enabling us to identify the targets of the UPS in these conformational diseases - may now pave the way for intervention and treatment of AD.
Peter J. Whitehouse
Quality of Life: The bridge from the cholinergic basal forebrain to cognitive science and bioethics
Abstract: Our paper on loss of neurons in the Nucleus Basalis of Meynert (now considered part of the cholinergic basal forebrain) in Alzheimer disease (AD) stimulated scientific interest in this little studied brain region. Our subsequent studies associated pathology in the basal forebrain with other dementias, such as Parkinson’s disease, and with neurotransmitter receptor changes, such as in nicotinic receptors. We and many others worked to develop medications to treat AD through cholinergic mechanisms and eventually four cholinesterase inhibitors were approved. However the effect sizes of currently available drugs are modest and ethical issues in conducting research in dementia are challenging. In Cleveland we came to focus on the goals of improving quality of life and the importance on non-pharmacological approaches to treatment. International efforts were organized to improve the efficiency of drug development and to focus on important cultural and pharmacoeconomic issues. Eventually I became concerned about the very way we conceive AD and related concepts like MCI (mild cognitive impairment). As the hundredth anniversary of the first case approaches I am helping to organize meetings to reflect deeply on what we have learned and how to imagine creating a more positive future for persons affected by what I used to call AD.