The present invention discloses a method and an in-vivo assay system useful for the identification and testing of modulating agents as well as for the validation of therapies of neurodegenerative diseases associated with the formation of neurofibrillary tangles, in particular Alzheimer's disease. The present invention is based on the surprising finding that injection of .beta.-amyloid A.beta..sub.42 fibrils into brains of P301L mutant tau transgenic mice caused several-fold increases in the numbers and an accelerated production of neurofibrillary tangles in cell bodies predominantly within the amygdala. The induced neurofibrillary tangles occurred as early as 18 days after A.beta..sub.42 injections and displayed striking features of neurofibrillary tangles of several human neurodegenerative diseases, particularly Alzheimer's disease.