Main interests
Alzheimer’s disease (AD) is the most frequent synaptic disorder of the increasingly aging population. It is uncertain if the current therapeutic strategies based on late disease events and on research on familial forms of AD (fAD) will benefit the 99% of AD patients with unknown etiology. The late onset AD etiology is likely multifactorial, with aging being the biggest risk factor and genetic predisposition likely accelerating the disease onset.
The lack of successful therapies is in part due to the irreversible neurodegeneration already installed in the affected patients. We have shown that early synaptic dysfunction is a major reversible target (Almeida et. Al, 2005; Snyder et-al 20015).
Now our focus is to determine the causal mechanisms of synaptic dysfunction in the common Late-onset Alzheimer’s disease (LOAD). Aging is the main risk factor for AD, but the contribution of intrinsic neuronal aging to LOAD is unkown. Several endocytic regulators were identified as LOAD genetic risk factors indicating endolysosomal dysfunction as a major cellular AD mechanism however how it contributes to LOAD is unclear.
Thus, we hypothesize that neuronal endolysosomal dysfunction, either by aging or genetic risk factors, contributes to synaptic dysfunction in LOAD.
Research Areas
Our aims are:
1. Does deregulation of endosomal sorting drive synaptic dysfunction?
BIN1 and CD2AP, two top ten GWAS genes are regulators of endosomal trafficking and actin dynamics(20, 28). We found that Bin1 and CD2AP loss of function increase endogenous Aβ production(21). We showed that both enhance APP access to β- and γ-secretases at sorting endosomes by distinct mechanisms of endosomal sorting(21).
We are investigating the impact of AD variants in Bin1 and CD2AP on intraneuronal Aβ42 by semi-quantitative single cell immunofluorescence, on APP and its secretases trafficking by pulse-chase assays, morphological and molecular analysis using imaging and biochemistry assays using mouse primary neurons, or alternatively in Neuro2a cell line we are developing in collaboration with C. Brito (iBET) induced human neurons edited with AD variants using Crispr/CAS9 in collaboration with A. Gontijo (CEDOC).
2. Does neuronal endocytic trafficking become dysfunctional with neuronal aging and have an impact on synapses?
Multiple mechanisms intrinsic to aging neurons likely drive synaptic decline. We are investigating investigate how age-related endocytic trafficking dysfunction drives aging-synaptic decline using in mouse primary neurons aged in vitro.
Overall, we aim to identify novel cellular and molecular mechanisms that deregulate the endolysosomal pathway in normal aging and upon LOAD genetic risk, establishing causality between aging and genetic variants and the development of LOAD.
Ultimately, we hope to determine the mechanisms underlying synaptic decline in aging neurons to identify novel therapeutic targets to delay or prevent AD.
Discover more about the Neuronal Trafficking in Aging Lab
- À procura do segredo da longevidade
Projects
2019-2022 Understanding the Impact of a Late-Onset Alzheimer's Disease Mutation in CD2AP on Synapses
Alzheimer's Association
PI: Cláudia G. Almeida
2018-2022 LYSOCIL: Excel in Rare Diseases’ Research: Focus on LYSOsomal Disorders and CILiopathies
European Union’s Horizon Twinning project 2020 (No 811087)
Partner: Cláudia G. Almeida
2018 Impact of the genetic risk factor CD2AP on the development of Alzheimer's disease
INOVA4Health
CO-PI: Cláudia G. Almeida
2017 Impact of the genetic risk factor CD2AP on the development of Alzheimer's disease
Award Maratona da Saúde
PI: Cláudia G. Almeida
2016-2019 NAB3
Cofund JPND/H2020
Partner: Cláudia G. Almeida
2015 Recapitulating late-onset Alzheimer’s disease in a three dimensional human neural cell model
Award Santander/Totta and Universidade NOVA de Lisboa
PI: Cláudia G. Almeida
2013-2017 Marie Curie Integration grant - TrafficInAD
Marie Curie Actions, EC
PI: Cláudia G. Almeida
2013 - 2018 Investigador FCT exploratory project
Foundation for Science and Technology, Portugal
PI: Cláudia G. Almeida
2013 - 2016 Imaging the structure and dynamics of molecules and complexes in living organisms
(RECI/BEX-BCM/0083/2012)
Foundation for Science and Technology, Portugal
PI: Nuno Moreno, Partner: Cláudia G. Almeida
Publications
- Burrinha T., Martinsson I., Gomes R., Terrasso AP, Gouras GK, Almeida CG. Upregulation of APP endocytosis by neuronal aging drives amyloid-dependent synapse loss. J Cell Sci 1 May 2021; 134 (9): jcs255752. doi: 10.1242/jcs.255752 Download PDF
- Ubelmann F, Burrinha T, Salavessa L, Gomes R, Ferreira C, Moreno N, Guimas Almeida C. (2016) Bin1 and CD2AP polarise the endocytic generation of beta-amyloid. EMBO Rep. 2016 Nov 28. pii: e201642738. [Epub ahead of print]
- Almeida CG, Yamada A, Tenza D, Louvard D, Raposo G, Coudrier E. Myosin 1b promotes the formation of post-Golgi carriers by regulating actin assembly and membrane remodelling at the trans-Golgi network. Nat Cell Bio. 2011, Jun 12;13(7):779-89. (10 citations; IF = 19.407)
- Tampellini D, Magrane J, Takahashi RH, Li F, Lin MT, Almeida CG, Gouras GK. Internalized Antibodies to the Abeta Domain of APP Reduce Neuronal Abeta and Protect against Synaptic Alterations. J Biol Chem. 2007 Jun 29;282(26):18895-906. (61 citations; IF = 3.603)
- Sahlin C, Lord A, Magnusson K, Englund H, Almeida CG, Greengard P, Nyberg F, Gouras GK, Lannfelt L, Nilsson LN. The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase. J Neurochem. 2007 May;101(3):854-62. (22 citations; IF = 4.337)
- Almeida CG, Takahashi RH, Gouras GK. Aβ42 accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neuroscience. Apr 19;26(16):4277-88. (90 citations; IF = 7.271)
- Almeida CG, Tampellini D, Takahashi RH, Greengard P, Lin MT, Snyder EM, Gouras GK. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005 Nov;20(2):187-98 (145 citations; IF = 5.121)
- Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. (551 citations; IF = 14.191)
- Gouras GK, Almeida CG, Takahashi RH. Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease. Neurobiol Aging. 2005 Oct;26(9):1235-44. (125 citations; IF = 6.634)
- Stenh C, Englund H, Lord A, Johansson AS, Almeida CG, Gellerfors P, Greengard P, Gouras GK, Lannfelt L, Nilsson LN. Amyloid-beta oligomers are inefficiently measured by enzyme-linked immunosorbent assay. Ann Neurol. 2005 Jul;58(1):147-50. (48 citations; IF = 10.746)
- Li F, Calingasan NY, Yu F, Mauck WM, Toidze M, Almeida CG, Takahashi RH, Carlson GA, Flint Beal M, Lin MT, Gouras GK. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice.J Neurochem. 2004 Jun;89(5):1308-12. (110 citations; IF = 4.337)
- Takahashi RH, Almeida CG, Kearney PF, Yu F, Lin MT, Milner TA, Gouras GK. Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci. 2004 Apr 7;24(14):3592-9. (211 citations; IF = 7.271)
- Almeida CG, de Mendonca A., Cunha R.A., Ribeiro J.A. “Adenosine promotes neuronal recovery from reactive oxygen species induced lesion in rat hippocampal slices”. Neurosci Lett. 2003 339:127-30. (25 citations; IF = 2.055)
Collaborations
- Catarina Brito, ITQB
- Tiago Gil Oliveira, ICVS | 3B's
- Orfeu Flores, STAB Vida
- Henrique Girão, IBILI
Team photos
2021
2018
2017
2015
2014
2013
. 1 Research Fellowship @ Cláudia Almeida Lab
Research fellowship for Bachelor holders, under the supervision of Cláudia Almeida, head of the Neuronal Trafficking in Aging lab. Deadline is August 28, 2021.
6-month fellowship, with renewal possibilities, in the scope of the project "Recapitulating late-onset Alzheimer's disease in a three dimensional human neural cell model". Candidates should have:
- Bachelor Degree or equivalent in the field of Biochemistry or equivalent; final grade above 16 required;
- Enrolment in a master’s degree in the field of Neuroscience or Biomedical Research;
- Research experience in molecular and cellular mechanisms of neuronal trafficking dysfunction relevant for Alzheimer’s disease (demonstrated on CV).
Applications have to be submitted by email, to applications@nms.unl.pt, mentioning the reference Grant DAI/2021/09 in the Subject of the message and must be formalized by sending a Letter of Motivation accompanied by the following documents: Curriculum vitae, qualifications certificate, proof of inscription on a Master´s degree, and other supporting documents considered relevant.
More info here. Notices in English and Portuguese also available.
. 1 Post-Doc Fellowhsip @ Cláudia Almeida Lab
An international call for one postdoctoral research fellowship, under the supervision of Cláudia Almeida, leader of the Neuronal Trafficking in Aging Lab, is now open. Deadline is September 5, 2021.
The Postdoctoral Researcher, expected to have a recent PhD in neurosciences, will establish a novel synaptic function for CD2AP and determine the impact of a Alzheimer’s mutation in CD2AP on synapses. The experimental approach includes microscopy-based cell biology and neurosciences assays, electrophysiology recordings using multi-electrode arrays, as well as proteomic analysis. The postdoc is expected to be creative, and to show initiative, and will be mentored to become the project leader, to write manuscripts and to communicate at international meetings.
Applications must be formalized, mandatorily, by sending a Motivation Letter accompanied by the following documents to applications@nms.unl.pt, mentioning the reference of Bolsa DAI / 2021/05 in the Subject:
- Motivation Letter in English
- Short Curriculum Vitae identifying the elements indicated in the desired profile when possible
- Copy of the qualifications certificate.
More info here.