Te puru metilīni, te tau, me te amiroiti: he aha i rerekē ai ngā tukanga whakakore pūmua

Ki te pātai koe he aha tā te puru metilīni ki ngā pūmua o te mate Alzheimer, ka rangona he whakautu kotahi e kīia ana me te tino māia, ahakoa e tika ana kia rangona he whakautu e toru, me ngā here o ia whakautu. I roto i tētahi ipu whakamātautau, ka whakararu i te piri o te tau ki a ia anō. I tētahi tauira kiore, ka whakaheke i te amiroiti wairewa, engari kāore e whakarerekē i te tau. I tētahi atu, ka whakaheke i te hohe o te whākōkī nāna tonu te amiroiti e whakaputa. He kitenga tūturu ēnei katoa. Kāore tētahi o ēnei e whakaatu ana i te kōrero katoa, ā, kāore e puta katoa i te kararehe kotahi i te wā kotahi. Ka wehe tēnei tuhinga i ēnei kitenga e toru, kia kore ai te hua o tētahi whakamātau e whakahuahia hei taunakitanga mō tētahi atu.

Ko ngā kaipānui e hiahia ana ki te tirohanga whānui ake mō te mahi a te puru metilīni i roto i ngā pūtau me tīmata ki reira. Ko ngā kaipānui e hiahia ana ki te mōhio mēnā i āwhina ēnei mahi i ngā tūroro me pānui ngā taunakitanga haumanu mō te mate Alzheimer, nā te mea kei reira te wāhi mō ngā putanga o ngā whakamātautau ki te tangata. Kāore tēnei tuhinga e tāruarua i aua taunakitanga.

Nō ngā whakamātautau whakahuihui te kitenga mō te tau

Ko te kōrero tawhito rawa o ēnei kōrero e toru i ahu mai i ngā rangahau kore pūtau mō te tau, te pūmua e hanga ana i ngā pōkai kaka io. I te whakamātautau here tau-tau, ka hui ngā wāhanga tau hei kaka tōrino takirua, ā, ka aukati ngā waikano phenothiazine, tae atu ki te puru metilīni, i taua huihuinga i ngā kukūtanga moroiti-mōra iti. Nā ngā rangahau matū koiora o muri mai i whakamārama ā-matū tēnei: ka hāora te waikano i ngā toenga cysteine o te tau, ā, mā konei ka pūmau ake tōna āhua waeine kotahi, ka tāmi hoki i ngā kaka iti ka tupu mēnā kāore taua pānga. Ko ngā kukūtanga aukati kua pūrongotia mō te whakahuihui tau kei te takiwā mai i ngā tau mati kotahi ki ngā tekau iti o te moroiti-mōra. He whānuitanga whai take tēnei mō ngā kōrero katoa ka whai ake.

Kia mōhio ki te momo kerēme nei. Kāore tēnei e kōrero ana mō te whakaputanga tau, te tāpiritanga rōpū phosphate ki te tau i roto i tētahi roro ora, te whakakorenga tau rānei. E kī ana, i raro i ngā āhuatanga kua tautuhia i roto i tētahi ipu whakamātautau, ka ārai te waikano kua hāoratia i te whakararanga o te tau. He hua tika, whāiti, whai take hoki tēnei. Ka tīmata te raruraru ina whakawhānuitia hei kōrero whānui e mea ana ka whakakore te puru metilīni i ngā āhuatanga māuiui e pā ana ki te tau, nā te mea kāore ngā raraunga kararehe e tautoko i taua kōrero.

Nō ngā kiore 3xTg-AD te kitenga mō te proteasome, ā, i wehe ngā pānga ki te amiroiti i ngā pānga ki te tau

Ko te whakamātau tino mārama i whakaatu i te rerekētanga o ngā putanga ine ko tētahi rangahau kai 16 wiki ki ngā kiore e mau ana i ngā irakētanga Alzheimer e toru. Mai i te ono marama te pakeke, ka kai ngā kararehe i te kai kei roto te puru metilīni, ā, e toru ngā mea i inea ngātahitia e ngā kairangahau: te proteasome, ngā taumata amiroiti, me te tau.

I rerekē te hohe o te proteasome. I piki te hohe rite ki te chymotrypsin mā te takiwā o te hauwhā, me te hohe rite ki te trypsin mā te takiwā o te haurua, engari kāore te hohe whakakōkī tuatoru i rerekē nui ā-tatauranga. I heke te amiroiti-beta 40 me te 42 wairewa, ia mea mā te takiwā o te hauwhā. I whakamāori ngā kaituhi i tēnei hei pikinga o te whakakorenga, kaua hei hekenga o te whakaputanga, nā te mea kāore te pūmua tōmua me ngā wāhanga i hua mai i tōna tukatuka i rerekē, ā, i pai ake te ako me te mahara i te whakamātautau aromatawai o te ara kōpikopiko wai.

Kātahi ko ngā putanga kāore i rerekē ngātahi. Kāore te amiroiti kore-wairewa i rerekē. Kāore te whakawaikano hei kite i ngā putunga amiroiti i rerekē. Kāore te tapeke tau tangata me te tau whai phosphate i te threonine 181 i rerekē, ā, kāore hoki te noho o te tau ki ngā wāhi hē i rerekē. Kāore hoki ngā inenga mitokōria i rerekē: kāore he pānga nui ā-tatauranga ki te hohe o te cytochrome-c oxidase, ki te pūmua oxidase, ki te ATP rānei. Nō reira, i tēnei tauira, i raro i tēnei hōtaka hoatu, i whakapiki te puru metilīni i te rua o ngā hohe proteasome e toru, i whakaheke i te amiroiti wairewa, i whakaora i tētahi inenga whanonga, ā, kāore i whakarerekē i ngā putanga ine tau, te amiroiti kore-wairewa, me ngā putanga ine mitokōria i whakamātauria.

He here kotahi ka whakakoi i te aronga nei, kāore e whakangoikore. Kāore anō ēnei kiore kia whakawhanake i ngā huinga tau i te pakeke i whakamātauria ai. Nō reira, kāore e taea e tēnei whakamātau te whakaatu kāore te puru metilīni e whai pānga ki ngā pōkai tau. E whakaatu ana ka taea te amiroiti wairewa te heke ahakoa kāore ngā putanga ine tau e rerekē. Koinei tonu te momo hua e hiahiatia ana mō tēnei kaupapa: i rerekē tētahi pūmua, kāore tētahi atu i rerekē. Mēnā i tae mai koe me te whakapono ka whakakore ngātahi te whakahohenga proteasome nā te puru metilīni i ngā pūmua tohu matua e rua, mā tēnei rangahau taua whakapono e whakatika.

Nō ngā kiore PSAPP kaumātua te kitenga mō te whakaputanga amiroiti, ā, e whakahē ana i te tukanga o mua

He rōpū kē, he tauira kē, ā, he whakamārama tauaro mō te tukanga o mua atu. I tētahi rangahau hoatu mā te ngongo ki te puku mō te toru marama ki ngā kiore PSAPP 15 marama te pakeke, nā te horopeta ā-waha o ia rā, arā, 3 mg/kg, i whakaheke te nui o ngā putunga amiroiti puta noa i ngā wāhanga roro mā te takiwā o te hautoru ki te haurua. I whakaheke hoki i ētahi hautanga amiroiti, tae atu ki ngā oligomer i inea mā tētahi whakamātautau motuhake. Engari i konei, ko te tukanga i whakaarohia ko te hekenga o te whakaputanga, kaua ko te whakakorenga tere ake: i heke te pūmua BACE1 i te roro, i heke tōna hua C99, engari kāore te RNA karere i heke. E tohu ana tēnei ki tētahi pānga i te taumata pūmua, kaua ki te hekenga o te whakapuakitanga ira.

I whakapakari ngā rangahau pūtau i taua whakamārama. I tētahi whakamātautau kore pūtau me te whākōkī i hangaia mā te hangarau DNA whakahono, i aukati tika te puru metilīni i te BACE1. Ā, i ngā pūtau kākano o te hāmuta e whakaputa ana i te pūmua tōmua amiroiti tangata, i heke te amiroiti 40 me te 42 i tukuna ki waho i ngā kukūtanga tae rawa ki te 1.56 moroiti-mōra, engari kāore te pūmua tōmua ake i rerekē. Whakatauritea tēnei ki te rangahau o mua, kāore nei ngā wāhanga i hua mai i te tukatuka i te pūmua tōmua i rerekē, ā, i kīia ko te whakakorenga te take. Kāore e taea e ēnei e rua te whakamārama i te tukanga kotahi e pā ana ki ngā horopaki katoa, nā te mea he rerekē ngā tauira, ngā pakeke, ngā horopeta, ngā ara hoatu, me ngā roanga. Koinei te aronga. Ka pā te puru metilīni ki te amiroiti mā te whakaputanga i tētahi whakaritenga whakamātau, mā te whakakorenga i tētahi atu. Ki te whakahua i tētahi me te kore e whakaatu i tōna whakaritenga whakamātau, ka whakapohehe.

Kotahi te matū, he maha ngā ūnga: te hononga mā te hāoratanga cysteine

Ka whakamārama tētahi ara rangahau tuatoru me pēhea te puta o te tukanga matū hāora-whakaheke kotahi i roto i ngā kōrero mō ngā pūmua kāore i te hono. I tētahi rangahau matū koiora mō te aukati caspase, i whakakore te puru metilīni i te hohe o te caspase-6 mā te hāora i tōna cysteine whakakōkī hei waikawa sulfenic. I whakamanahia tēnei mā te ine tūāwhiorangi papatipu, ā, ko te kukūtanga mō te haurua o te pānga mōrahi i tata ki te 10.6 moroiti-mōra. I aukatia hoki te caspase-3 i tētahi kukūtanga ōrite. I āta hono ngā kaituhi i tēnei ki ngā tuhinga rangahau tau: ko taua tukanga matū hāora cysteine i whakaarohia hei pupuri i te tau hei waeine kotahi, ka taea hoki te whakakore i te hohe o tētahi whākōkī wāwāhi pūmua e whakawhirinaki ana ki te cysteine, ā, e īnaki ana ngā kukūtanga whai pānga.

He whakamārama ātaahua tēnei, ā, he whakatūpato hoki. Ko tētahi rāpoi hohe hāora-whakaheke e hāora ana i ngā cysteine e wātea ana, ka whai i te ūnga neke atu i te kotahi i ngā kukūtanga e whai pānga ana. Ko te kōrero mō te wawahanga o ngā huinga tau, te kōrero mō te caspase, me ētahi atu pea, e whakamahi ana i te mahi matū kotahi ki ngā mea rerekē. Nā taua mahi kotahi, kāore ngā kitenga e taea te whakawhiti hei whakakapi i tētahi ki tētahi. Ko te tikanga, mā te horopeta me te horopaki e whakatau ko tēhea ūnga te mea whai take, ā, ko te hoatu horopeta mō te wā roa ki te whai i tētahi tukanga e whakawhirinaki ana ki te cysteine, ka pā pea ki ētahi atu. I āta whakaarahia tēnei take e ngā kaituhi o te rangahau caspase. Ko ngā pātai e pā ana ki te kōwhiringa ūnga a te matū hāora-whakaheke o te puru metilīni, te tikanga o te whakahohenga proteasome mō ētahi atu pūmua kua whakahuihuia, me te rerekētanga pea o te huinga ūnga nā te hoatu horopeta mō te wā roa, e tika ana kia kōrerotia motuhaketia.

Te tukanga mō ia putanga ine: nō tēhea tauira ia kitenga

Pānuihia te ripanga, he rārangi ki te rārangi, ā, ka mārama te akoranga. Kāore he rārangi kotahi e rerekē ana i ngā tīwae katoa. Ko te hua kaha rawa mō te whakaputanga amiroiti i ahu mai i te rangahau kāore rawa i whakamātauria te proteasome. Ko te hua kaha rawa mō te proteasome i ahu mai i te rangahau kāore rawa i rerekē te tukatuka i te pūmua tōmua. Ko te hua mō te tau kei roto te nuinga i ngā ipu whakamātautau, ā, kei roto hoki i te tukanga matū e pā tahi ana ki ngā whākōkī kei waho i te ūnga i whakaritea. Ko te tangata e whakakotahi ana i ēnei tīwae hei kerēme kotahi, arā, ka whakakore te puru metilīni i te kāwai katoa o ngā pūmua māuiui, e tuhi ana i tētahi arotake o te whakamātau kāore rawa i mahia.

Ka pā hoki taua āta wehewehe ki ngā tūroro. He pātai motuhake te pātai mēnā ka hua mai he painga haumanu i ēnei tukanga katoa, me ōna ake whakamātautau, me ōna ake whakatau. Kei ngā taunakitanga haumanu mō te mate Alzheimer te whakautu, kaua i konei.