Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis

Topic: Brain proteins, microglia and lab models

The early endosome is the first vacuolar compartment along the endocytic pathway. It is the site of internalization and initial processing of amyloid precursor protein (APP) and apolipoprotein E (ApoE), two proteins of etiological importance in Alzheimer's disease, and a putative site of beta-amyloid peptide (Abeta) formation. Here, we identify early endosomes in human pyramidal neurons, using specific compartmental markers and morphometry, and show that in Alzheimer's disease individual endosomes display up to 32-fold larger volumes than the normal average. Endosomal enlargement contributed to an average 2.5-fold larger total endosomal volume per neuron, implying a marked increase in endocytic activity. Endosomal alterations were evident in most pyramidal neurons in Alzheimer brain, detectable at early stages of the disease but absent in several other neurodegenerative disorders examined. In addition, mature and proenzyme forms of the proteases cathepsin B and cathepsin D, a candidate APP secretase, were identified in most early endosomes in Alzheimer brains but were detectable in only a minor proportion of endosomes in normal brain. Expression of the cation-dependent 46 kDa mannose 6-phosphate receptor was elevated in pyramidal neurons of Alzheimer brains, which could be a possible basis for the altered cathepsin trafficking pattern. Enhanced endocytic activity, coupled with increased trafficking to endosomes of proteases, which may have the ability under pathological conditions to generate Abeta, constitutes a potential mechanism by which beta-amyloidogenesis may become accelerated in sporadic AD and also be subject to influences by ApoE.

@article{cataldo1997-9236226,
  author  = {Cataldo, A. M. and Barnett, J. L. and Pieroni, C. and Nixon, R. A.},
  title   = {{Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis}},
  journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
  year    = {1997},
  doi     = {10.1523/jneurosci.17-16-06142.1997},
  pmid    = {9236226},
  url     = {https://doi.org/10.1523/jneurosci.17-16-06142.1997}
}

Key findings

• Endosomal enlargement contributed to an average 2.5-fold larger total endosomal volume per neuron, implying a marked increase in endocytic activity.
• Endosomal alterations were evident in most pyramidal neurons in Alzheimer brain, detectable at early stages of the disease but absent in several other neurodegenerative disorders examined.
• In addition, mature and proenzyme forms of the proteases cathepsin B and cathepsin D, a candidate APP secretase, were identified in most early endosomes in Alzheimer brains but were detectable in only a minor proportion of endosomes in normal brain.
• Expression of the cation-dependent 46 kDa mannose 6-phosphate receptor was elevated in pyramidal neurons of Alzheimer brains, which could be a possible basis for the altered cathepsin trafficking pattern.
• Enhanced endocytic activity, coupled with increased trafficking to endosomes of proteases, which may have the ability under pathological conditions to generate Abeta, constitutes a potential mechanism by which beta-amyloidogenesis may become accelerated in sporadic AD and also be subject to influences by ApoE.

Why it matters

This brain tissue study found that early endosomes in neurons from Alzheimer's brains were enlarged and contained more of certain proteases than in normal brains, suggesting increased endocytic activity. The authors propose this may be a mechanism for increased beta-amyloid formation, but it is descriptive pathology, not a treatment.

New to this subject? Start with our plain-English guide: Genetics →

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1523/jneurosci.17-16-06142.1997
• PubMed: 9236226
• Original source →
• Free full text: PubMed Central →

Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease Nature · 1995-06-01 · usefulness score 64/100 · Genetics

Later studies that cite this one

18 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• Down syndrome Nature reviews. Disease primers · 2020-02-06 · usefulness score 56/100 · How common it is
• Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations The American journal of pathology · 2000-07-01 · usefulness score 52/100 · Genetics
• Alzheimer Disease Pathogenesis: Insights From Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species Frontiers in neuroscience · 2019-06-21 · usefulness score 51/100 · Down syndrome and Alzheimer's
• Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy Autophagy · 2016-11-04 · usefulness score 51/100 · Brain tissue and pathology
• Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome Archives of pathology & laboratory medicine · 2001-04-01 · usefulness score 51/100 · Down syndrome and Alzheimer's
• Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF Science advances · 2023-07-26 · usefulness score 50/100 · Down syndrome and Alzheimer's
• Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects The American journal of pathology · 2008-06-05 · usefulness score 49/100 · Down syndrome and Alzheimer's
• Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements The Journal of neuroscience : the official journal of the Society for Neuroscience · 2007-08-01 · usefulness score 48/100 · Lewy body dementia

Related studies in Genetics

• Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death Neurobiology of aging · 2002-09-01 · usefulness score 36/100
• Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes Neuron · 2017-09-01 · usefulness score 38/100
• Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer's disease brains eLife · 2015-02-04 · usefulness score 43/100
• Apolipoprotein E, ɛ4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region Human Molecular Genetics · 1994-01-01 · usefulness score 48/100
• Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms Alzheimer's & dementia : the journal of the Alzheimer's Association · 2017-09-21 · usefulness score 47/100
• Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios Molecular Psychiatry · 2026-05-29 · usefulness score 41/100

Also tagged “precursor”

1,337 studies in the library carry the topic tag “precursor”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,337 tagged studies.

• Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice The Journal of neuroscience : the official journal of the Society for Neuroscience · 2000-05-01 · usefulness score 44/100 · Risk genes beyond APOE
• Potential Diagnostic Value of Red Blood Cells α-Synuclein Heteroaggregates in Alzheimer's Disease Molecular neurobiology · 2019-03-02 · usefulness score 43/100 · Biomarkers
• Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease Molecular neurodegeneration · 2021-07-23 · usefulness score 50/100 · Genetics

Studies sharing this one's topic tags

• APOE4 homozygosity represents a distinct genetic form of Alzheimer's disease Nature Medicine · 2024-05 · usefulness score 61/100 · shares: precursor, apoe, amyloid-beta
• APOE2 is associated with longevity independent of Alzheimer's disease eLife · 2020-10-19 · usefulness score 65/100 · shares: precursor, apoe, amyloid-beta
• Retraction Note: A specific amyloid-beta protein assembly in the brain impairs memory Nature · 2024-06-24 · usefulness score 16/100 · shares: precursor, apoe, amyloid-beta
• NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice Nature · 2012-12-19 · usefulness score 62/100 · shares: precursor, apoe, amyloid-beta
• Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1 The Lancet Healthy Longevity · 2025-11-27 · usefulness score 63/100 · shares: precursor, apoe, amyloid-beta

Similar studies

• Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease 2002 · Risk genes beyond APOE
• Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease 1993 · Genetics
• Production and increased detection of amyloid beta protein and amyloidogenic fragments in brain microvessels, meningeal vessels and choroid plexus in Alzheimer's disease 1996 · Risk genes beyond APOE
• Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase 2000 · Risk genes beyond APOE
• Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo 2008 · Risk genes beyond APOE
• Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients 2004 · Risk genes beyond APOE

More on Genetics

• A review that covers this ground Entorhinal cortex astrocytes in early Alzheimer disease: Human evidence, cross-species circuit rationale, and translational boundaries Journal of Neuropathology & Experimental Neurology · 2026-08-18 · usefulness score 28/100
• Newest in this subject APH-1A and CDK5 Expression Correlates with Tau Hyperphosphorylation and Its Attenuation by Brahmi and Donep-M in STZ induced Alzheimer’s Disease Model Research Square · 2026-10-31 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Integrative systems biology identifies shared neuroimmune co-expression programmes across pulmonary tuberculosis and Alzheimer's disease Research Square · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Genetics →