Neuritic Alterations and Neural System Dysfunction in Alzheimer's Disease and Dementia with Lewy Bodies

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders that share progressive dementia as the common major clinical symptom. Damages to memory-related brain structures are the likely pathological correlate, and in both illnesses deposition of amyloidogenic proteins are present mainly within these limbic structures. Amyloid-β–positive plaques and phospho-tau–positive neurofibrillary tangles are the main feature of AD and α-synuclein–positive Lewy bodies and Lewy neurites are found in DLB. Interestingly the associated proteins also interfere with synaptic function and synaptic plasticity. Here, we propose that the same neuronal circuits are disturbed within the hippocampal formation in AD and DLB and that in both diseases the associated proteins might lead to changes in synaptic plasticity and function. Thus both classic neuropathological changes and cellular dysfunctions might contribute to the cognitive impairments in AD and DLB.

[1]  B. Hyman,et al.  Nigral and Cortical Lewy Bodies and Dystrophic Nigral Neurites in Parkinson's Disease and Cortical Lewy Body Disease Contain α-synuclein Immunoreactivity , 1998, Journal of neuropathology and experimental neurology.

[2]  J. Trojanowski,et al.  Relationship between plaques, tangles, and dystrophic processes in Alzheimer's disease , 1995, Neurobiology of Aging.

[3]  C. Cotman,et al.  Apoptosis Decision Cascades and Neuronal Degeneration in Alzheimer’s Disease , 1998, Neurobiology of Aging.

[4]  B. Hyman,et al.  Dementia with Lewy Bodies , 1998, Journal of the American Geriatrics Society.

[5]  D L Rosene,et al.  Subicular input from temporal cortex in the rhesus monkey. , 1979, Science.

[6]  B. Hyman,et al.  α-Synuclein–enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons , 2001, Neuroscience.

[7]  L. Serpell,et al.  Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Michael J. Rowan,et al.  Amyloid-β oligomers: their production, toxicity and therapeutic inhibition , 2001 .

[9]  Bengt Winblad,et al.  Defective brain microtubule assembly in Alzheimer??s disease , 1987 .

[10]  Hidefumi Ito,et al.  Immunocytochemical Co‐localization of the Proteasome in Ubiquitinated Structures in Neurodegenerative Diseases and the Elderly , 1997, Journal of neuropathology and experimental neurology.

[11]  G. Collingridge,et al.  Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein , 1999, Neuropharmacology.

[12]  Michel Goedert,et al.  Identification of two distinct synucleins from human brain , 1994, FEBS letters.

[13]  Nutan Sharma,et al.  TorsinA and heat shock proteins act as molecular chaperones: suppression of α‐synuclein aggregation , 2002, Journal of neurochemistry.

[14]  D. Neill,et al.  Aggregates from mutant and wild‐type α‐synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β‐sheet and amyloid‐like filaments , 1998, FEBS letters.

[15]  Christian Haass,et al.  Subcellular Localization of Wild-Type and Parkinson's Disease-Associated Mutant α-Synuclein in Human and Transgenic Mouse Brain , 2000, The Journal of Neuroscience.

[16]  A. Alzheimer.  Uber eine eigenartige Erkrankung der Hirnrinde , 1907 .

[17]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[18]  S. Davis,et al.  Generation of Aggregated β-Amyloid in the Rat Hippocampus Impairs Synaptic Transmission and Plasticity and Causes Memory Deficits , 2001, The Journal of Neuroscience.

[19]  G. Lynch,et al.  Synaptic rearrangement in the dentate gyrus: histochemical evidence of adjustments after lesions in immature and adult rats. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[21]  A. Jonas,et al.  Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes* , 1998, The Journal of Biological Chemistry.

[22]  M. Citron,et al.  alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. , 1999, The Journal of biological chemistry.

[23]  V. Uversky,et al.  Stabilization of Partially Folded Conformation during α-Synuclein Oligomerization in Both Purified and Cytosolic Preparations* , 2001, The Journal of Biological Chemistry.

[24]  John Hardy,et al.  Amyloid, the presenilins and Alzheimer's disease , 1997, Trends in Neurosciences.

[25]  J. Trojanowski,et al.  Monoclonal antibodies to purified cortical lewy bodies recognize the mid‐size neurofilament subunit , 1997, Annals of neurology.

[26]  R A Crowther,et al.  alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  B. Hyman,et al.  The Lack of Accumulation of Senile Plaques or Amyloid Burden in Alzheimer's Disease Suggests a Dynamic Balance Between Amyloid Deposition and Resolution , 1993, Journal of neuropathology and experimental neurology.

[28]  P J McLean,et al.  Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson's disease-linked mutations. , 2000, The Journal of biological chemistry.

[29]  L. Mucke,et al.  Synaptotrophic effects of human amyloid β protein precursors in the cortex of transgenic mice , 1994, Brain Research.

[30]  R. Perrin,et al.  Interaction of human alpha-Synuclein and Parkinson's disease variants with phospholipids. Structural analysis using site-directed mutagenesis. , 2000, The Journal of biological chemistry.

[31]  G. V. Van Hoesen,et al.  Perforant pathway changes and the memory impairment of Alzheimer's disease , 1986, Annals of neurology.

[32]  R. Doms,et al.  Intracellular APP processing and A beta production in Alzheimer disease. , 1999, Journal of neuropathology and experimental neurology.

[33]  Peter T. Lansbury,et al.  Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease , 1998, Nature Medicine.

[34]  M G Spillantini,et al.  Alpha-synuclein in Lewy bodies. , 1997, Nature.

[35]  M. Rowan,et al.  Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. , 2002, Biochemical Society transactions.

[36]  P. S. St George-Hyslop,et al.  Defective membrane interactions of familial Parkinson's disease mutant A30P α-synuclein , 2002 .

[37]  L. Lue,et al.  Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease , 1999 .

[38]  Christina A. Wilson,et al.  Intracellular APP Processing and Aβ Production in Alzheimer Disease , 1999 .

[39]  T. Shimahara,et al.  Alzheimer Amyloid β-Peptide Inhibits the Late Phase of Long-Term Potentiation through Calcineurin-Dependent Mechanisms in the Hippocampal Dentate Gyrus , 2002, Neurobiology of Learning and Memory.

[40]  L. Squire,et al.  The medial temporal lobe memory system , 1991, Science.

[41]  Mrc Psych,et al.  Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop , 1996 .

[42]  J. Trojanowski,et al.  Synucleins Are Developmentally Expressed, and α-Synuclein Regulates the Size of the Presynaptic Vesicular Pool in Primary Hippocampal Neurons , 2000, The Journal of Neuroscience.

[43]  A. Morris,et al.  Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. , 1998, Biochemistry.

[44]  R. Jakes,et al.  Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of α‐synuclein protein implicated in Parkinson's disease , 1998, FEBS letters.

[45]  B T Hyman,et al.  Entorhinal cortex pathology in Alzheimer's disease , 1991, Hippocampus.

[46]  B. Hyman,et al.  Clinical and Neuropathological Correlates of Dementia with Lewy Bodies , 2000, Annals of the New York Academy of Sciences.

[47]  J Q Trojanowski,et al.  A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly* , 2001, The Journal of Biological Chemistry.

[48]  Arnold B. Scheibel,et al.  Dendritic sprouting in Alzheimer's presenile dementia , 1978, Experimental Neurology.

[49]  Akihiko Iwai,et al.  The precursor protein of non-Aβ component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system , 1995, Neuron.

[50]  Y. Ihara,et al.  Lewy bodies are ubiquitinated , 1988, Acta Neuropathologica.

[51]  B. Hyman,et al.  Subcellular localization of alpha-synuclein in primary neuronal cultures: effect of missense mutations. , 2000, Journal of neural transmission. Supplementum.

[52]  B. Hyman,et al.  Characterization of the Precursor Protein of the Non-Aβ Component of Senile Plaques (NACP) in the Human Central Nervous System , 1996, Journal of neuropathology and experimental neurology.

[53]  A. Nappi,et al.  Alzheimer ' s Disease : Cell-Specific Pathology Isolates the Hippocampal Formation , 2022 .

[54]  P. S. St George-Hyslop,et al.  Defective membrane interactions of familial Parkinson's disease mutant A30P alpha-synuclein. , 2002, Journal of molecular biology.

[55]  B. Hyman,et al.  Disordered proteins in dementia , 2002, Annals of medicine.

[56]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[57]  David F. Clayton,et al.  The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease , 1998, Trends in Neurosciences.

[58]  C. Cotman,et al.  Synaptic plasticity and functional stabilization in the hippocampal formation: possible role in Alzheimer's disease. , 1988, Advances in neurology.

[59]  E. Masliah,et al.  Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[60]  John Q. Trojanowski,et al.  Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease , 2001, Science.

[61]  J. Kim.  Evidence that the precursor protein of non-A beta component of Alzheimer's disease amyloid (NACP) has an extended structure primarily composed of random-coil. , 1997, Molecules and cells.

[62]  J. Storm-Mathisen.  Choline acetyltransferase and acetylcholinesterase in fascia dentata following lesion of the entorhinal afferents. , 1974, Brain research.

[63]  D. Dickson,et al.  Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease , 1991, Neurology.

[64]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[65]  C. Cotman,et al.  Enhancing the self-repairing potential of the CNS after injury. , 1984, Central nervous system trauma : journal of the American Paralysis Association.

[66]  C. Masters,et al.  Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease , 1999, Annals of neurology.

[67]  B T Hyman,et al.  Alz‐50 Antibody recognizes alzheimer‐related neuronal changes , 1988, Annals of neurology.

[68]  J. Trojanowski,et al.  Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. , 2002, Science.

[69]  Scott M. Hammond,et al.  Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization , 1997, Current Biology.

[70]  C. Cotman,et al.  Plasticity of hippocampal circuitry in Alzheimer's disease. , 1985, Science.

[71]  E. Masliah,et al.  Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer's disease. , 1996, The American journal of pathology.

[72]  R A Crowther,et al.  Synthetic filaments assembled from C-terminally truncated alpha-synuclein. , 1998, FEBS letters.

[73]  C. Lavedan.  The synuclein family. , 1998, Genome research.

[74]  M. Mesulam,et al.  A Plasticity‐Based Theory of the Pathogenesis of Alzheimer's Disease , 2000, Annals of the New York Academy of Sciences.

[75]  Michel Goedert,et al.  Alpha-synuclein and neurodegenerative diseases , 2001, Nature Reviews Neuroscience.

[76]  C. Cotman,et al.  Brain function, synapse renewal, and plasticity. , 1982, Annual review of psychology.

[77]  R. Nicoll,et al.  Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[78]  Michael Alford,et al.  Patterns of aberrant sprouting in alzheimer's disease , 1991, Neuron.

[79]  D. Selkoe,et al.  In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692-->Gly) Alzheimer's disease. , 2001, The Biochemical journal.

[80]  P. Blumbergs,et al.  In Situ and in Vitro Study of Colocalization and Segregation of α-Synuclein, Ubiquitin, and Lipids in Lewy Bodies , 2000, Experimental Neurology.

[81]  M. Goedert,et al.  Binding of α-Synuclein to Brain Vesicles Is Abolished by Familial Parkinson’s Disease Mutation* , 1998, The Journal of Biological Chemistry.

[82]  Deepak N. Pandya,et al.  Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey. III. Efferent connections , 1975, Brain Research.

[83]  R. Crowther,et al.  α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies , 1998 .

[84]  D. Clayton,et al.  Synucleins in synaptic plasticity and neurodegenerative disorders , 1999, Journal of neuroscience research.

[85]  P. Coleman,et al.  Dendritic growth in the aged human brain and failure of growth in senile dementia. , 1979, Science.

[86]  Bradley T. Hyman,et al.  Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease , 1992, Neurology.

[87]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[88]  K. Duff,et al.  Behavioral Changes in Transgenic Mice Expressing Both Amyloid Precursor Protein and Presenilin-1 Mutations: Lack of Association with Amyloid Deposits , 1999, Behavior genetics.

[89]  R. Krüger,et al.  Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. , 1998, Nature genetics.

[90]  B. Hyman,et al.  α-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining , 2000, Acta Neuropathologica.

[91]  T. Bliss,et al.  Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice , 1999, Nature Neuroscience.

[92]  Martí-Massó Jf,et al.  [Dementia with Lewy bodies]. , 2000, Neurologia.

[93]  M. Hasselmo,et al.  Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[94]  C. Cotman,et al.  Cell biology of synaptic plasticity. , 1984, Science.

[95]  J Q Trojanowski,et al.  Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[96]  G. Lynch,et al.  Induced acetylcholinesterase-rich layer in rat dentate gyrus following entorhinal lesions. , 1972, Brain research.

[97]  Douglas L. Rosene,et al.  The Hippocampal Formation of the Primate Brain , 1987 .

[98]  M. Citron,et al.  Both Familial Parkinson’s Disease Mutations Accelerate α-Synuclein Aggregation* , 1999, The Journal of Biological Chemistry.

[99]  J Q Trojanowski,et al.  Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. , 1998, The American journal of pathology.

[100]  H. Stanley,et al.  Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[101]  Y. Bailly,et al.  Synaptic beta-amyloid precursor proteins increase with learning capacity in rats. , 1997, Neuroscience.

[102]  B. Hyman,et al.  Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies , 1999, Neurology.

[103]  R. Anthony Crowther,et al.  Synthetic filaments assembled from C‐terminally truncated α‐synuclein , 1998 .

[104]  Richard Paylor,et al.  Synaptic Vesicle Depletion Correlates with Attenuated Synaptic Responses to Prolonged Repetitive Stimulation in Mice Lacking α-Synuclein , 2002, The Journal of Neuroscience.

[105]  D. Selkoe,et al.  Alzheimer's Disease: A Central Role for Amyloid , 1994, Journal of neuropathology and experimental neurology.

[106]  Dominic M. Walsh,et al.  Protofibrillar Intermediates of Amyloid β-Protein Induce Acute Electrophysiological Changes and Progressive Neurotoxicity in Cortical Neurons , 1999, The Journal of Neuroscience.

[107]  R. Malinow,et al.  APP Processing and Synaptic Function , 2003, Neuron.

[108]  E. Mori.  [Dementia with Lewy bodies]. , 2000, Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics.

[109]  L. Lue,et al.  Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. , 1999, The American journal of pathology.

[110]  R A Crowther,et al.  Tau Proteins and Neurofibrillary Degeneration , 1991, Brain pathology.

[111]  Y. Bailly,et al.  Synaptic β-amyloid precursor proteins increase with learning capacity in rats , 1997, Neuroscience.

[112]  Bradley T. Hyman,et al.  Distribution of Alzheimer‐type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease , 1992, Neurology.

[113]  C. Finch,et al.  Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? , 2001, Trends in Neurosciences.

[114]  G. V. Van Hoesen,et al.  Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease , 1987, Annals of neurology.

[115]  G. V. Van Hoesen,et al.  The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. , 1991, Cerebral cortex.

[116]  O. Steward,et al.  Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat , 1976, The Journal of comparative neurology.

[117]  G. W. Hoesen,et al.  Neural Systems of the Non‐human Primate Forebrain Implicated in Memory a , 1985 .

[118]  Kang Hu,et al.  High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation , 2000, The Journal of Neuroscience.

[119]  V. Uversky,et al.  Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. , 2001, Biochemistry.

[120]  G. V. Van Hoesen,et al.  Hippocampal formation: anatomy and the patterns of pathology in Alzheimer's disease. , 1990, Progress in brain research.

[121]  B. Yankner.  Mechanisms of Neuronal Degeneration in Alzheimer's Disease , 1996, Neuron.

[122]  J. Morris,et al.  Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease , 1996, The Journal of Neuroscience.

[123]  G. Halliday,et al.  Selective hippocampal neuron loss in dementia with Lewy bodies , 2002, Annals of neurology.

[124]  L. Villa-komaroff,et al.  Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. , 1989, Science.

[125]  P. Lansbury,et al.  NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. , 1996, Biochemistry.

[126]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[127]  C. Lippa,et al.  Alzheimer's disease and Lewy body disease: A comparative clinicopathological study , 1994, Annals of neurology.

[128]  Abnormal, ubiquitinated cortical neurites in patients with diffuse Lewy body disease , 1996, Neuroscience Letters.