title: Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75(NTR) immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California 92093-0624, USA.
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Ruben
authors.initials: R
authors.lastname: Vazquez-Roque
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Chandra
authors.initials: C
authors.lastname: Inglis
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Margaret
authors.initials: M
authors.lastname: Fahnestock
authors.forename: Edith
authors.initials: E
authors.lastname: Doppler
authors.forename: Philip
authors.initials: P
authors.lastname: Novak
authors.forename: Herbert
authors.initials: H
authors.lastname: Moessler
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000627:therapeutic use*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D018678:Cholinergic Agents / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism
chemical_list: D000596:Amino Acids; D016564:Amyloid beta-Protein Precursor; D018678:Cholinergic Agents; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C006952:cerebrolysin; D002795:Choline O-Acetyltransferase; D020917:Receptor, trkA