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• W1984652813 abstract "The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer’s disease (AD). We suggest that synaptic changes are central to the disease process. Amyloid beta and tau form fibrillar lesions that are the classical hallmarks of AD. Recent data indicate that both molecules may have normal roles at the synapse, and that the accumulation of soluble toxic forms of the proteins at the synapse may be on the critical path to neurodegeneration. Further, the march of neurofibrillary tangles through brain circuits appears to take advantage of recently described mechanisms of transsynaptic spread of pathological forms of tau. These two key phenomena, synapse loss and the spread of pathology through the brain via synapses, make it critical to understand the physiological and pathological roles of amyloid beta and tau at the synapse. The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer’s disease (AD). We suggest that synaptic changes are central to the disease process. Amyloid beta and tau form fibrillar lesions that are the classical hallmarks of AD. Recent data indicate that both molecules may have normal roles at the synapse, and that the accumulation of soluble toxic forms of the proteins at the synapse may be on the critical path to neurodegeneration. Further, the march of neurofibrillary tangles through brain circuits appears to take advantage of recently described mechanisms of transsynaptic spread of pathological forms of tau. These two key phenomena, synapse loss and the spread of pathology through the brain via synapses, make it critical to understand the physiological and pathological roles of amyloid beta and tau at the synapse. Brains of AD patients are characterized by accumulation of amyloid beta (Aβ) into senile plaques and hyperphosphorylated tau into neurofibrillary tangles (Figure 1). Although these defining lesions were first described over a century ago by Alois Alzheimer (Alzheimer, 1907Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde.Allgemeine Zeitschrife Psychiatrie. 1907; 64: 146-148Google Scholar), their link to brain degeneration has remained elusive. Genetic evidence from rare familial forms of AD strongly supports accumulation of Aβ as causative to the disease process. Mutations in the amyloid precursor protein (APP) and in presenilins 1 and 2, which are essential in generating Aβ, cause familial, early-onset AD (Tanzi, 2012Tanzi R.E. The genetics of Alzheimer disease.Cold Spring Harb. Perspect. Med. 2012; 2: a006296Crossref Scopus (43) Google Scholar). However, there are challenges to the amyloid hypothesis suggesting that Aβ may not play a central role in the degenerative process after disease initiation. The accumulation of plaques in the brain does not correlate with cognitive impairments in patients (Giannakopoulos et al., 2003Giannakopoulos P. Herrmann F.R. Bussière T. Bouras C. Kövari E. Perl D.P. Morrison J.H. Gold G. Hof P.R. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease.Neurology. 2003; 60: 1495-1500Crossref PubMed Google Scholar, Ingelsson et al., 2004Ingelsson M. Fukumoto H. Newell K.L. Growdon J.H. Hedley-Whyte E.T. Frosch M.P. Albert M.S. Hyman B.T. Irizarry M.C. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.Neurology. 2004; 62: 925-931Crossref PubMed Google Scholar), a large number of people without any cognitive impairment have substantial accumulations of plaques in their brains (Perez-Nievas et al., 2013Perez-Nievas B.G. Stein T.D. Tai H.-C. Dols-Icardo O. Scotton T.C. Barroeta-Espar I. Fernandez-Carballo L. de Munain E.L. Perez J. Marquie M. et al.Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology.Brain. 2013; 136: 2510-2526Crossref PubMed Scopus (6) Google Scholar), and the reduction of plaque load in the brain by immunotherapy does not result in cognitive improvement in AD patients (Holmes et al., 2008Holmes C. Boche D. Wilkinson D. Yadegarfar G. Hopkins V. Bayer A. Jones R.W. Bullock R. Love S. Neal J.W. et al.Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial.Lancet. 2008; 372: 216-223Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar). Tangles, on the other hand, do correlate strongly with cognitive decline and with neuronal and synapse loss (Arriagada et al., 1992Arriagada P.V. Marzloff K. Hyman B.T. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease.Neurology. 1992; 42: 1681-1688Crossref PubMed Google Scholar, Duyckaerts et al., 1998Duyckaerts C. Colle M.A. Dessi F. Piette F. Hauw J.J. Progression of Alzheimer histopathological changes.Acta Neurol. Belg. 1998; 98: 180-185PubMed Google Scholar, Giannakopoulos et al., 2003Giannakopoulos P. Herrmann F.R. Bussière T. Bouras C. Kövari E. Perl D.P. Morrison J.H. Gold G. Hof P.R. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease.Neurology. 2003; 60: 1495-1500Crossref PubMed Google Scholar, Ingelsson et al., 2004Ingelsson M. Fukumoto H. Newell K.L. Growdon J.H. Hedley-Whyte E.T. Frosch M.P. Albert M.S. Hyman B.T. Irizarry M.C. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.Neurology. 2004; 62: 925-931Crossref PubMed Google Scholar); however, mutations in tau cause frontotemporal dementia, not AD (Goedert and Jakes, 2005Goedert M. Jakes R. Mutations causing neurodegenerative tauopathies.Biochim. Biophys. Acta. 2005; 1739: 240-250Crossref PubMed Scopus (176) Google Scholar). Of the neuropathological features of the disease, synapse loss correlates most strongly with dementia, implicating it as important to the disease process (Koffie et al., 2011Koffie R.M. Hyman B.T. Spires-Jones T.L. Alzheimer’s disease: synapses gone cold.Mol. Neurodegener. 2011; 6: 63Crossref PubMed Scopus (40) Google Scholar). As well as frank synapse loss, it is becoming clear from animal models that dysfunction of synapses and impaired synaptic plasticity are also key components of the neurodegenerative process in AD and that both Aβ and tau contribute to this degeneration (Crimins et al., 2013Crimins J.L. Pooler A. Polydoro M. Luebke J.I. Spires-Jones T.L. The intersection of amyloid β and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer’s disease.Ageing Res. Rev. 2013; 12: 757-763Crossref PubMed Scopus (7) Google Scholar). Here we will discuss recent hypotheses about how synaptic structure and function are disrupted by Aβ and tau in the AD brain, contributing to cognitive impairment. Further, we will discuss the important role of synapses in the spread of pathology through the brain. In the healthy adult brain, synaptic plasticity is thought to be what allows learning and the formation of memories. The most striking symptom of AD is memory loss, so it is not surprising that the areas of the brain essential for memory, and the synaptic plasticity that forms the neurochemical and structural basis of memory, degenerates. In particular, the hippocampus and neocortex are important for learning and memory (Dudai and Morris, 2013Dudai Y. Morris R.G. Memorable trends.Neuron. 2013; 80: 742-750Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar), and the circuitry connecting them is particularly impacted by AD pathology (Figure 2). During the course of AD, synaptic plasticity is altered, and many of the mechanisms involved in normal plasticity become dysregulated, leading to synapse dysfunction and collapse. The concept of synaptic plasticity and its role in learning was put forward by Ramon y Cajal, who noted that the number of neurons in the brain did not appear to change significantly over our lifespan, making it unlikely that new memories were the result of new neurons being born and integrated into the brain. Instead, he proposed that changes in the strength of connections between existing neurons could be the mechanism for memory formation (Cajal, 1894Cajal S.R.Y. The Croonian Lecture: La fine structure des centres nerveux.Proc. R. Soc. Lond. 1894; 55: 444-468Crossref Google Scholar, Jones, 1994Jones E.G. Santiago Ramón y Cajal and the Croonian Lecture, March 1894.Trends Neurosci. 1994; 17: 190-192Abstract Full Text PDF PubMed Google Scholar). In 1949, Hebb expanded upon this idea when he postulated that the connection between two neurons would be strengthened if they activate simultaneously and weakened if they activate separately (Hebb, 1949Hebb D.O. The Organization of Behavior: A Neuropsychological Theory. John Wiley & Sons, New York1949Google Scholar). The description of long-term potentiation (LTP) and its counterpart, long-term depression (LTD) from studies of animal brain slices, provides molecular understanding of the phenomenon of synapse strengthening or weakening. LTP is a specific, long-lasting increase in the strength of synaptic transmission when the pre- and postsynaptic neurons are activated simultaneously, which was first described in rabbit hippocampus (Bliss and Gardner-Medwin, 1973Bliss T.V. Gardner-Medwin A.R. Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path.J. Physiol. 1973; 232: 357-374PubMed Google Scholar). The mechanisms of LTP can be pre- or postsynaptic, but postsynaptic mechanisms seem most affected in AD models. There are early and late phases of LTP, with the early phase dependent upon protein kinase activation causing several changes to synaptic AMPA receptors (AMPARs) including phosphorylation, enhanced activity, and insertion of new receptors into the postsynaptic density. During late-phase LTP, increased levels of calcium at the postsynaptic site and persistent activation of kinases (importantly PKC, PKMζ, and CamKIIα, which converge on ERK) lead to activation of transcription factors including CREB. This in turn causes production of proteins (including locally translated proteins in “tagged” synapses), which are involved in new dendritic spine formation (Bliss et al., 2003Bliss T.V. Collingridge G.L. Morris R.G. Introduction. Long-term potentiation and structure of the issue.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 607-611Crossref PubMed Scopus (57) Google Scholar, Frey and Morris, 1997Frey U. Morris R.G. Synaptic tagging and long-term potentiation.Nature. 1997; 385: 533-536Crossref PubMed Scopus (712) Google Scholar, Redondo and Morris, 2011Redondo R.L. Morris R.G. Making memories last: the synaptic tagging and capture hypothesis.Nat. Rev. Neurosci. 2011; 12: 17-30Crossref PubMed Scopus (101) Google Scholar, Sanhueza and Lisman, 2013Sanhueza M. Lisman J. The CaMKII/NMDAR complex as a molecular memory.Mol. Brain. 2013; 6: 10Crossref PubMed Scopus (16) Google Scholar). LTD is a weakening of synaptic strength following a stimulus. LTD can occur via several mechanisms, which unsurprisingly have effects opposite to those seen in LTP, including internalization of AMPA receptors (Collingridge et al., 2010Collingridge G.L. Peineau S. Howland J.G. Wang Y.T. Long-term depression in the CNS.Nat. Rev. Neurosci. 2010; 11: 459-473Crossref PubMed Scopus (174) Google Scholar, Dudek and Bear, 1992Dudek S.M. Bear M.F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade.Proc. Natl. Acad. Sci. USA. 1992; 89: 4363-4367Crossref PubMed Scopus (824) Google Scholar, Massey and Bashir, 2007Massey P.V. Bashir Z.I. Long-term depression: multiple forms and implications for brain function.Trends Neurosci. 2007; 30: 176-184Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). NMDA receptor (NMDAR)-dependent LTD, which appears to be most affected in AD, depends on calcium influx, calcineurin activation, and nonapoptotic caspase activation (Li et al., 2010Li Z. Jo J. Jia J.-M. Lo S.-C. Whitcomb D.J. Jiao S. Cho K. Sheng M. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization.Cell. 2010; 141: 859-871Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, Mulkey et al., 1993Mulkey R.M. Herron C.E. Malenka R.C. An essential role for protein phosphatases in hippocampal long-term depression.Science. 1993; 261: 1051-1055Crossref PubMed Google Scholar). LTD is thought to be important for clearing old memory traces and in situations requiring behavioral flexibility (Collingridge et al., 2010Collingridge G.L. Peineau S. Howland J.G. Wang Y.T. Long-term depression in the CNS.Nat. Rev. Neurosci. 2010; 11: 459-473Crossref PubMed Scopus (174) Google Scholar). Interestingly, this forgetting aspect of LTD may be hijacked during AD as very similar molecular mechanisms are involved in LTD and AD-related synapse degeneration, in particular the central role of calcineurin activation. Along with potentiation and depotentiation of synaptic strength, structural changes occur in response to brain plasticity. LTP has been associated with the formation of new dendritic spines, increases in perforated postsynaptic densities (receiving more than one presynaptic input), and with the enlargement of spine heads (Bosch and Hayashi, 2012Bosch M. Hayashi Y. Structural plasticity of dendritic spines.Curr. Opin. Neurobiol. 2012; 22: 383-388Crossref PubMed Scopus (54) Google Scholar, Maletic-Savatic et al., 1999Maletic-Savatic M. Malinow R. Svoboda K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity.Science. 1999; 283: 1923-1927Crossref PubMed Scopus (765) Google Scholar, Nägerl et al., 2004Nägerl U.V. Eberhorn N. Cambridge S.B. Bonhoeffer T. Bidirectional activity-dependent morphological plasticity in hippocampal neurons.Neuron. 2004; 44: 759-767Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, Van Harreveld and Fifkova, 1975Van Harreveld A. Fifkova E. Swelling of dendritic spines in the fascia dentata after stimulation of the perforant fibers as a mechanism of post-tetanic potentiation.Exp. Neurol. 1975; 49: 736-749Crossref PubMed Google Scholar). Conversely, LTD has been associated with spine shrinkage and loss (Bastrikova et al., 2008Bastrikova N. Gardner G.A. Reece J.M. Jeromin A. Dudek S.M. Synapse elimination accompanies functional plasticity in hippocampal neurons.Proc. Natl. Acad. Sci. USA. 2008; 105: 3123-3127Crossref PubMed Scopus (84) Google Scholar, Matsuzaki et al., 2004Matsuzaki M. Honkura N. Ellis-Davies G.C. Kasai H. Structural basis of long-term potentiation in single dendritic spines.Nature. 2004; 429: 761-766Crossref PubMed Scopus (877) Google Scholar, Nägerl et al., 2004Nägerl U.V. Eberhorn N. Cambridge S.B. Bonhoeffer T. Bidirectional activity-dependent morphological plasticity in hippocampal neurons.Neuron. 2004; 44: 759-767Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, Zhou et al., 2004Zhou Q. Homma K.J. Poo M.M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses.Neuron. 2004; 44: 749-757Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar), with recent fascinating data indicating that this process may involve nonapoptotic caspase-3 activation (D’Amelio et al., 2012D’Amelio M. Sheng M. Cecconi F. Caspase-3 in the central nervous system: beyond apoptosis.Trends Neurosci. 2012; 35: 700-709Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, Li et al., 2010Li Z. Jo J. Jia J.-M. Lo S.-C. Whitcomb D.J. Jiao S. Cho K. Sheng M. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization.Cell. 2010; 141: 859-871Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). Under conditions of environmental enrichment, substantial numbers of new dendritic spines (and corresponding excitatory synapses) and new dendritic branches form on pyramidal neurons (Mora et al., 2007Mora F. Segovia G. del Arco A. Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain.Brain Res. Brain Res. Rev. 2007; 55: 78-88Crossref Scopus (134) Google Scholar, Nithianantharajah and Hannan, 2006Nithianantharajah J. Hannan A.J. Enriched environments, experience-dependent plasticity and disorders of the nervous system.Nat. Rev. Neurosci. 2006; 7: 697-709Crossref PubMed Scopus (482) Google Scholar). During the course of Alzheimer’s disease, the normal function of synapses is impaired, synapses are eliminated, and pathological proteins are transported through synapses. Before exploring these phenomena, we will present background on the neuropathology of AD and then follow with how pathological lesions affect synapses. Structural changes in the AD brain have been classified as “positive” lesions, i.e., the accumulation of plaques, tangles, neuropil threads, dystrophic neurites, cerebral amyloid angiopathy (CAA), and other lesions that are deposited in AD patients’ brains, and “negative” lesions, comprising the massive atrophy due to neuron loss and the degeneration of neurites and synapses (Serrano-Pozo et al., 2011aSerrano-Pozo A. Frosch M.P. Masliah E. Hyman B.T. Neuropathological alterations in Alzheimer disease.Cold Spring Harb. Perspect. Med. 2011; 1: a006189Crossref Scopus (25) Google Scholar). Each of these lesions is present in a characteristic pattern in AD, which provides some clues about the relationship between the lesions and disease progression and symptoms. There are also structural changes in the neuropil associated with plaques and tangles, which are thought to contribute to cognitive impairments (Figure 2). Senile plaques, first described by Alzheimer using Bielchowsky silver staining on brain sections from a patient with dementia, were determined in the early 1980s to be largely composed of the amyloid beta peptide (Glenner and Wong, 1984Glenner G.G. Wong C.W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.Biochem. Biophys. Res. Commun. 1984; 120: 885-890Crossref PubMed Google Scholar, Masters and Selkoe, 2012Masters C.L. Selkoe D.J. Biochemistry of amyloid β-protein and amyloid deposits in Alzheimer disease.Cold Spring Harb. Perspect. Med. 2012; 2: a006262Crossref Scopus (35) Google Scholar). Neuritic, or dense-cored, plaques have a dense center of amyloid surrounded by a halo of silver-positive neurites. After the sequencing of the peptide and development of antibodies to Aβ, it was found that Aβ also aggregates in “diffuse” plaques of several different morphologies (Dickson and Vickers, 2001Dickson T.C. Vickers J.C. The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer’s disease.Neuroscience. 2001; 105: 99-107Crossref PubMed Scopus (91) Google Scholar, Gomez-Isla et al., 2008Gomez-Isla T. Spires T. De Calignon A. Hyman B.T. Neuropathology of Alzheimer’s disease.Handb. Clin. Neurol. 2008; 89: 233-243Crossref PubMed Scopus (17) Google Scholar, Serrano-Pozo et al., 2011aSerrano-Pozo A. Frosch M.P. Masliah E. Hyman B.T. Neuropathological alterations in Alzheimer disease.Cold Spring Harb. Perspect. Med. 2011; 1: a006189Crossref Scopus (25) Google Scholar). From cross-sectional studies of postmortem human brain, it appears that senile plaque deposition occurs early in the disease process and proceeds slowly, beginning in the neocortex and progressing through the allocortex, then to the diencephalon, striatum, and basal forebrain cholinergic nuclei, followed by progression to brainstem nuclei and finally to the cerebellum (Thal et al., 2002Thal D.R. Rüb U. Orantes M. Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD.Neurology. 2002; 58: 1791-1800Crossref PubMed Google Scholar). Watching plaques appear in real time in the brains of mice that overexpress AD-associated APP and PS1 mutations with in vivo multiphoton imaging surprisingly reveals that individual plaques coalesce from soluble Aβ remarkably rapidly. Plaques form within 24 hr and surrounding neurites begin to curve and degenerate within days after plaque formation (Meyer-Luehmann et al., 2008Meyer-Luehmann M. Spires-Jones T.L. Prada C. Garcia-Alloza M. de Calignon A. Rozkalne A. Koenigsknecht-Talboo J. Holtzman D.M. Bacskai B.J. Hyman B.T. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease.Nature. 2008; 451: 720-724Crossref PubMed Scopus (416) Google Scholar). Dense plaques are toxic to the surrounding brain parenchyma, causing a number of phenomena that may contribute to synapse dysfunction and loss. Many neurites surrounding plaques exhibit swollen, dystrophic morphologies and often contain aggregates of phospho-tau and multiple cellular components that likely accumulate due to disrupted cellular transport (Serrano-Pozo et al., 2011aSerrano-Pozo A. Frosch M.P. Masliah E. Hyman B.T. Neuropathological alterations in Alzheimer disease.Cold Spring Harb. Perspect. Med. 2011; 1: a006189Crossref Scopus (25) Google Scholar, Woodhouse et al., 2005Woodhouse A. West A.K. Chuckowree J.A. Vickers J.C. Dickson T.C. Does beta-amyloid plaque formation cause structural injury to neuronal processes?.Neurotox. Res. 2005; 7: 5-15Crossref PubMed Scopus (11) Google Scholar). The trajectories of axons and dendrites, which are usually fairly straight, are disrupted in the vicinity of amyloid plaques in mouse models of AD, which may impact synaptic integration of signal (Le et al., 2001Le R. Cruz L. Urbanc B. Knowles R.B. Hsiao-Ashe K. Duff K. Irizarry M.C. Stanley H.E. Hyman B.T. Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption.J. Neuropathol. Exp. Neurol. 2001; 60: 753-758Crossref PubMed Google Scholar, Spires et al., 2005Spires T.L. Meyer-Luehmann M. Stern E.A. McLean P.J. Skoch J. Nguyen P.T. Bacskai B.J. Hyman B.T. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy.J. 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Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.Neurology. 2004; 62: 925-931Crossref PubMed Google Scholar, McLellan et al., 2003McLellan M.E. Kajdasz S.T. Hyman B.T. Bacskai B.J. In vivo imaging of reactive oxygen species specifically associated with thioflavine S-positive amyloid plaques by multiphoton microscopy.J. Neurosci. 2003; 23: 2212-2217PubMed Google Scholar, Serrano-Pozo et al., 2011bSerrano-Pozo A. Mielke M.L. Gómez-Isla T. Betensky R.A. Growdon J.H. Frosch M.P. Hyman B.T. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease.Am. J. Pathol. 2011; 179: 1373-1384Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). While plaques are associated with disrupted neurite morphology, gliosis, and oxidative stress, less is known about the impact of NFT on the surrounding neuropil. Neurofibrillary tangles and neuropil threads are formed of aggregated tau protein. 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Acta. 2005; 1739: 280-297Crossref PubMed Scopus (175) Google Scholar). The deposition of tangles occurs in a hierarchical fashion beginning in the entorhinal cortex and progressing through the hippocampal formation, association cortices, and only affecting primary sensory areas in late stages of the disease (Arnold et al., 1991Arnold S.E. Hyman B.T. Flory J. Damasio A.R. Van Hoesen G.W. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease.Cereb. Cortex. 1991; 1: 103-116Crossref PubMed Google Scholar, Braak and Braak, 1991Braak H. Braak E. Neuropathological stageing of Alzheimer-related changes.Acta Neuropathol. 1991; 82: 239-259Crossref PubMed Google Scholar). NFT deposition in human AD correlates with cognitive decline and neuronal loss (Arriagada et al., 1992Arriagada P.V. Marzloff K. Hyman B.T. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease.Neurology. 1992; 42: 1681-1688Crossref PubMed Google Scholar, Duyckaerts et al., 1998Duyckaerts C. Colle M.A. Dessi F. Piette F. Hauw J.J. Progression of Alzheimer histopathological changes.Acta Neurol. Belg. 1998; 98: 180-185PubMed Google Scholar, Giannakopoulos et al., 2003Giannakopoulos P. Herrmann F.R. Bussière T. Bouras C. Kövari E. Perl D.P. Morrison J.H. Gold G. Hof P.R. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease.Neurology. 2003; 60: 1495-1500Crossref PubMed Google Scholar, Gómez-Isla et al., 1997Gómez-Isla T. Hollister R. West H. Mui S. Growdon J.H. Petersen R.C. Parisi J.E. Hyman B.T. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease.Ann. Neurol. 1997; 41: 17-24Crossref PubMed Scopus (619) Google Scholar). The association of NFT with neuronal loss and the presence of ghost tangles—NFT that remain in the brain after the neuron has died—strongly suggest that at least some neurons with tangles die during the course of the disease; however, the amount of neuronal loss vastly exceeds the number of neurofibrillary tangles and ghost tangles within given brain regions, supporting the idea that a tangle is not necessary for neuron death in AD (Gómez-Isla et al., 1997Gómez-Isla T. Hollister R. West H. Mui S. Growdon J.H. Petersen R.C. Parisi J.E. Hyman B.T. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease.Ann. Neurol. 1997; 41: 17-24Crossref PubMed Scopus (619) Google Scholar). As intracellular lesions, NFT could be expected to have less impact on the surrounding environment than the extracellular accumulation of plaques; however, we recently observed gliosis in the vicinity of NFTs that correlates with disease progression (Serrano-Pozo et al., 2011bSerrano-Pozo A. Mielke M.L. Gómez-Isla T. Betensky R.A. Growdon J.H. Frosch M.P. Hyman B.T. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease.Am. J. Pathol. 2011; 179: 1373-1384Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Synapse loss in AD was described in the early 1990s by DeKosky and Scheff using electron microscopy and by Terry and Masliah using densitometry of immunostained synaptic proteins. These groups observed synapse loss in frontal cortex, temporal cortex, and dentate gyrus of the hippocampus and found that synapse loss is the strongest pathological correlate of dementia (DeKosky and Scheff, 1990DeKosky S.T. Scheff S.W. 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Interestingly, the entorhinal cortex, one of the earliest and most severely affected areas of the brain in terms of neuronal loss and tangle formation, does not appear to und" @default.
• W1984652813 created "2016-06-24" @default.
• W1984652813 creator A5068688487 @default.
• W1984652813 creator A5088747780 @default.
• W1984652813 date "2014-05-01" @default.
• W1984652813 modified "2023-10-17" @default.
• W1984652813 title "The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease" @default.
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