The protein tyrosine kinase, fyn, in Alzheimerʼs disease pathology

376

349

The abnormal phosphorylation of tau protein on serines and threonines is a hallmark characteristic of the neurofibrillary tangles of Alzheimer's disease (AD). The discovery that tau could be phosphorylated on tyrosine and evidence that A␤ signal transduction involved tyrosine phosphorylation led us to question whether tyrosine phosphorylation of tau occurred during the neurodegenerative process. In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. By developing both polyclonal and monoclonal probes specific for phospho-tyr18, we found that the phosphorylation of tau at tyr18 occurred at early developmental stages in mouse but was absent in the adult. Our phosphospecific probes also revealed that paired helical filament preparations exhibited phospho-tyr18 reactivity that was sensitive to phosphotyrosine-specific protein phosphatase treatment. Moreover, immunocytochemical studies indicated that tyrosine phosphorylated tau was present in the neurofibrillary tangles in AD brain. However, the staining pattern excluded neuropil threads and dystrophic neurites indicating that tyrosine phosphorylated tau was distributed in AD brain in a manner dissimilar from other abnormally phosphorylated tau. We also found evidence suggesting that differentially phosphorylated tau existed within degenerating neurons. Our data add new support for a role for fyn in the neurodegenerative process.

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 84%

Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease

Lee¹,

Thangavel²,

Sharma³

et al. 2004

376

349

“…mo, Months; IML, inner molecular layer. (Shirazi and Wood, 1993;Kohmura et al, 1998;Lauri et al, 1999;Chavis and Westbrook, 2001;Williamson et al, 2002;Grace and Busciglio, 2003).…”

Section: Fynmentioning

confidence: 99%

“…Fyn immunoreactivity (IR) is increased in AD brains (Shirazi and Wood, 1993), and genetic ablation of Fyn rendered hippocampal slices resistant to the neurotoxic effects of A␤ oligomers (Lambert et al, 1998). Here, we used genetic modulations of Fyn (overexpression vs ablation) to test the hypotheses that Fyn is involved in degenerative (synaptic deficits) and trophic (aberrant sprouting) effects of hAPP/A␤.…”

Section: Introductionmentioning

confidence: 99%

Fyn Kinase Modulates Synaptotoxicity, But Not Aberrant Sprouting, in Human Amyloid Precursor Protein Transgenic Mice

Chin

Palop²,

Yu³

et al. 2004

153

133

Alzheimer's disease (AD), the most common neurodegenerative disorder, results in progressive degeneration of synapses and aberrant sprouting of axon terminals. The mechanisms underlying these seemingly opposing cellular phenomena are unclear. We hypothesized that Fyn kinase may play a role in one or both of these processes because it is increased in AD brains and because it is involved in synaptic plasticity and axonal outgrowth. We investigated the effects of Fyn on AD-related synaptotoxicity and aberrant axonal sprouting by ablating or overexpressing Fyn in human amyloid precursor protein (hAPP) transgenic mice.On the fyn ϩ/ϩ background, hAPP/amyloid ␤ peptide (A␤) decreased hippocampal levels of synaptophysin-immunoreactive presynaptic terminals (SIPTs), consistent with previous findings. On the fyn Ϫ/Ϫ background, hAPP/A␤ did not affect SIPTs. SIPT reductions correlated with hippocampal A␤ levels in hAPP/fyn ϩ/ϩ , but not hAPP/fyn Ϫ/Ϫ , mice suggesting that Fyn provides a critical link between hAPP/A␤ and SIPTs. Furthermore, overexpression of Fyn exacerbated SIPT reductions in hAPP mice. We also found that the susceptibility of mice to hAPP/A␤-induced premature mortality was decreased by Fyn ablation and increased by Fyn overexpression. In contrast, axonal sprouting in the hippocampus of hAPP mice was unaffected. We conclude that Fyn-dependent pathways are critical in AD-related synaptotoxicity and that the pathogenesis of hAPP/A␤-induced neuronal alterations may be mechanistically heterogenous.Key words: Alzheimer's disease; amyloid ␤; Fyn kinase; synaptic deficits; signaling; sprouting; GAP-43; neurodegeneration IntroductionThe amyloid precursor protein (APP) is expressed in many cell types and is particularly abundant in synapses. One of its metabolites, amyloid ␤ peptide (A␤), suppresses synaptic transmission and may participate in the regulation of neuronal activity (Hsia et al., 1999;Kamenetz et al., 2003). Mutations in the human APP (hAPP) gene that lead to increased levels of A␤ cause autosomal dominant familial Alzheimer's disease (FAD) (Selkoe and Schenk, 2003). Of several species of A␤ produced, the 42-residue form (A␤1-42) is particularly susceptible to aggregation and is a primary constituent of neuritic amyloid plaques, pathological hallmarks of the disease (Selkoe and Schenk, 2003). Both FAD and sporadic AD are associated with a progressive degeneration of neurons and synapses (DeKosky and Scheff, 1990;Terry et al., 1999) and an aberrant sprouting of axon terminals (Geddes et al., 1985;Masliah et al., 1991;Arendt, 2001). The precise relationship between hAPP, A␤, plaques, synaptic loss, axonal sprouting, and cognitive decline in AD is unknown.Although amyloid plaques are a diagnostic feature of AD, growing evidence suggests that plaques may not be the primary cause of AD-related synaptic alterations and cognitive decline. In transgenic (TG) mice overexpressing hAPP/A␤ in neurons, synaptic and behavioral deficits are detectable well before plaque formation (Holcomb et al., 1999;Hsia et al., 199...

“…Indeed, Fyn activation occurs during engagement of integrins and glutamate receptors (Roskoski, 2004;Salter and Kalia, 2004), both of which have been implicated in A␤-induced disruption of synaptic function (Klein et al, 2001;Grace et al, 2002;Williamson et al, 2002). Furthermore, the distribution and levels of Fyn are altered in AD brains (Shirazi and Wood, 1993;Ho et al, 2004), and the toxic effects of A␤-derived diffusible ligands on murine hippocampal slices were blocked by the genetic ablation of Fyn (Lambert et al, 1998). Finally, ablation of Fyn decreased, whereas overexpression of Fyn increased, A␤-induced synaptotoxicity and premature mortality in human APP (hAPP) mice (Chin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease

Chin¹,

Palop²,

Puoliväli³

et al. 2005

292

255

Human amyloid precursor protein (hAPP) transgenic mice with high levels of amyloid-␤ (A␤) develop behavioral deficits that correlate with the depletion of synaptic activity-related proteins in the dentate gyrus. The tyrosine kinase Fyn is altered in Alzheimer's disease brains and modulates premature mortality and synaptotoxicity in hAPP mice. To determine whether Fyn also modulates A␤-induced behavioral deficits and depletions of synaptic activity-dependent proteins, we overexpressed Fyn in neurons of hAPP mice with moderate levels of A␤ production. Compared with nontransgenic controls and singly transgenic mice expressing hAPP or FYN alone, doubly transgenic FYN/hAPP mice had striking depletions of calbindin, Fos, and phosphorylated ERK (extracellular signal-regulated kinase), impaired neuronal induction of Arc, and impaired spatial memory retention. These deficits were qualitatively and quantitatively similar to those otherwise seen only in hAPP mice with higher A␤ levels. Surprisingly, levels of active Fyn were lower in high expresser hAPP mice than in NTG controls and lower in FYN/hAPP mice than in FYN mice. Suppression of Fyn activity may result from dephosphorylation by striatal-enriched phosphatase, which was upregulated in FYN/hAPP mice and in hAPP mice with high levels of A␤. Thus, increased Fyn expression is sufficient to trigger prominent neuronal deficits in the context of even relatively moderate A␤ levels, and inhibition of Fyn activity may help counteract A␤-induced impairments.